A Working Document

NIH Research And Other Efforts 

Related To 

The Menopausal Transition 

(Updated March 2005)

The Office of Research on Women’s Health 

and the 

 

Coordinating Committee on Research on Women’s Health 

National Institutes of Health

Report Compiled by:

Vivian W. Pinn, M.D., Director 

Office of Research on Women’s Health

Angela Bates, Program Analyst 

Office of Research on Women’s Health 
FOREWORD 

This represents the third compilation of National Institutes of Health funded research related to 

the menopausal transition, prepared by the Office of Research on Women’s Health in the Office 

of the Director. It is intended as a resource to describe in brief the many aspects of the 

menopausal transition that are currently the subject of research by NIH supported investigators. 

The report is prepared in collaboration with the women’s health liaison from each NIH institute 

and center (IC) who are all members of the NIH Coordinating Committee on Research on 

Women’s Health. The information received from each IC is incorporated as submitted. 

It is not intended that this report be exhaustive in the information it provides, but rather to reflect 

the vast interest of investigators in the menopausal transition and the extensive support of the 

NIH components of related research. 

 Vivian W. Pinn, M.D. 

 Associate Director for Research on Women’s Health 

 Director, Office of Research on Women’s Health 

 
TABLE OF CONTENTS 

INTRODUCTION

Coordinating Committee For Research on Women's Health Roster

Working Definitions of Menopause 

Web Resources on Menopause Hormone Therapy

Menopause Related Research

NATIONAL CANCER INSTITUTE (NCI) 1 

NATIONAL EYE INSTITUTE (NEI) 27 

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) 57 

NATIONAL INSTITUTE ON AGING (NIA) 63 

NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM (NIAAA) 89 

NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) 93 

NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) 97 

NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT (NICHD) 105 

NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS (NIDCD) 109 

NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH (NIDCR) 111 

NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES (NIDDK) 115 

NATIONAL INSTITUTE ON DRUG ABUSE (NIDA) 123 

NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES (NIEHS) 129 

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) 139 

NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) 141 

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) 165 

NATIONAL INSTITUTE OF NURSING RESEARCH (NINR) 171 

NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE (NCCAM) 179 

NATIONAL CENTER FOR RESEARCH RESOURCES (NCRR) 183 

 i 
Introduction 

The median age of women at cessation of menstrual bleeding is 50 to 51 years. With an average 

life expectancy of 79.7 years, most women can expect to spend one-third to one-half of their lives postmenopause. In the United States alone, there are an estimated 42.19 million women over age 50 

including 39.9 million postmenopausal women and 1.55 million women (4,255 per day) who reached 

menopause1

. Additionally, a woman who reaches age 54 can expect to reach the age of 84 years with 

more than two-thirds of the US population reaching 85 years or longera. By the year 2020, the number of 

US women over age 55 is expected to be 45.9 million. 

In 1998, there were more than 477 million postmenopausal women in the world, with 

approximately 9% expected to live to age 80. By 2025, the number of postmenopausal women is expected 

to rise to 1.1 billion. A women’s lifespan is expected to rise to 72 years worldwide by 2025 (82 in more 

developed countries). 

 According to a 1998 study, one in three women between ages 45 and 64 were on hormone 

therapy2

 (HT), and there were about 17.5 million women total taking HT to combat the biological effects 

of menopause3

. Understanding the biology, symptomology, and socio-cultural implications of the 

menopausal transition is essential in addressing the health concerns of the aging female population. 

Therefore, the Office of Research on Women’s Health (ORWH) is collaborating with NIH Institutes and 

Centers (IC) to develop a comprehensive report on NIH supported research and programs on the 

menopausal transition. 

Initial information for this report was obtained through queries of the NIH Computer Retrieval of 

Information on Scientific Projects database (CRISP) and the National Library of Medicine website, 

 

1

 North American Menopause Society, http://www.menopause.org/aboutmeno/sga.pdf 2

 “Health Concerns Across A Woman's Lifespan: The Commonwealth Fund 1998 Survey Of Women's Health.” 

Collins, K.S., Schoen, C., Joseph, S., Duchon, L., Simantov, E., Yellowitz, M. May 1999. 3

 “Study: Hormones Don’t Protect Women From Heart Disease.” Okie, S.Washington Post. July 24, 2001. 

 ii
www.ClinicalTrials.gov. Results of these queries were forwarded to the appropriate IC for verification, 

or revision. This report summarizes the basic science and clinical research, recent research results, and 

pending research studies on the menopausal transition currently funded by each Institute and Center, as 

provided through the Coordinating Committee on Research on Women’s Health (CCRWH) representative 

from each NIH component. 

Beginning with the definition of menopause as stated in the “World Health Report 1998,” 

published by the World Health Organization (WHO), this report provides a summary, by IC, of 

menopause related research currently being funded by the NIH. Five IC’s reported no current research on 

menopause: National Human Genome Research Institute (NHGRI), Fogarty International Center (FIC), 

National Institute of Biomedical Imaging and Bioengineering (NIBIB), Center for Scientific Review 

(CSR) and the National Library of Medicine (NLM). 

 iii
2005 COORDINATING COMMITTEE ON RESEARCH ON 

WOMEN'S HEALTH 

Institute/Center Representative Alternate

NIDA Cora Lee Wetherington Adele Roman 

NICHD Mona Rowe Estella Parrott

NHLBI Jacques Rossouw Barbara Liu, Cindy Palace 

NCRR Susan Kayar Sheila McClure

NIAMS Charisee Lamar Cheryl Kitt

NLM Gale Dutcher 

NIGMS Pamela Marino Paula Flicker

NIEHS Anne Sassaman Sheila Newton

NCI Anna Levy Cherie Nichols

NIA Lorraine Fitzsimmons Barbara Kellner

NINR Yvonne Bryan 

NINDS Linda Porter Brandy Fureman 

NHGRI Laura Rodriquez 

NEI Ellen S. Liberman Natalie Kurinij 

NIDCR Maria Canto Patricia Bryant, Ruth Nowjack-Raymer 

NIDCD Lana Shekim Amy Donahue

NIAID Diane Adger-Johnson Milton Hernandez 

NIDDK Eleanor Hoff Mary Hanlon

NIMH Catherine Roca Ernest Marquez 

NIAAA Denise Russo Diedra Roach

NIBIB Anthony Demsey Tinera Fobbs 

FIC Karen Hofman Sharon Hrynkow

CSR Denise Wiesch Elaine Sierra-Rivera 

Clinical Center Deborah Dozier-Hall Walter Jones

NCCAM Heather Miller 

NCMHD John Ruffin Mireille Kanda

OAR Vicki Cargill Denise Miles

OSE Bonnie Kalberer 

OC John Burklow Marin Allen 

OBSSR Virginia Cain Melba Reed

ODS Mary Frances Picciano 

OIR Joan Schwartz Barbara Vonderhaar

OIR Esther Sternberg 

OSP Cheryl McDonald Lana Skirboll 

OCL Tom Gallagher Walter Mitten

OEODM Joan Brogan Rose Pruitt

OPLA Anne Houser 

OITE Pat Sokolove

 iv
Working Definitions of Menopause

From the World Health Report, 1998 World Health Organization, Geneva, Switzerland 

TERM SOURCE

Menopause (natural menopause) WHO*

The term natural menopause is defined as the permanent cessation of 

menstruation resulting from the loss of ovarian follicular activity. Natural

menopause is recognized to have occurred after 12 consecutive months of 

amenorrhoea, for which there is no other obvious pathological or 

physiological cause. Menopause occurs with the final menstrual period 

(FMP), which is known with certainty only in retrospect a year or more 

after the event. An adequate biological marker for the event does not 

exist. 

Perimenopause WHO

The term perimenopause should include the period immediately prior to 

the menopause (when the endocrinological, biological, and clinical 

features of approaching menopause commence) and the first year after 

menopause. 

Menopausal transition WHO

The term menopausal transition should be reserved for that period of time

before the FMP when variability in the menstrual cycle is usually 

increased. 

Climacteric IMS**

This phase in the aging of women marks the transition from the 

reproductive phase to the non-reproductive state. This phase incorporates

the perimenopause by extending for a longer variable period before and 

after the perimenopause. 

Climacteric syndrome IMS

The climacteric is sometimes, but not necessarily always, associated with

symptomatology. When this occurs, it may be termed the "climacteric

syndrome." 

Premenopause WHO

The term premenopause is often used ambiguously to refer to the one or 

two years immediately before the menopause or to refer to the whole of

the reproductive period prior to the menopause. The group recommended 

that the term be used consistently in the latter sense to encompass the 

entire reproductive period up to the FMP. 

 v 
Postmenopause WHO

The term postmenopause is defined as dating from the FMP, regardless

of whether the menopause was induced or spontaneous. 

Premature menopause WHO 

Ideally, premature menopause should be defined as menopause that

occurs at an age more than two standard deviations below the mean 

estimated for the reference population. In practice, in the absence of 

reliable estimates of the distribution of age at natural menopause in 

populations in developing countries, the age of 40 years is frequently 

used as an arbitrary cut-off point, below which menopause is said to be 

premature. 

Induced menopause WHO 

The term, induced menopause, is defined as the cessation of 

menstruation, which follows either surgical removal of both ovaries (with 

or without hysterectomy) or iatrogenic ablation of ovarian function (e.g. 

by radiation or chemotherapy). 

*WHO – World Health Organization 

**IMS – International Menopause Society

 vi
Web Resources on Menopausal Hormone Therapy

National Institutes of Health 

http://www.nih.gov/PHTindex.htm 

National Heart, Lung & Blood Institute 

http://www.nhlbi.nih.gov/health/women/index.htm 

National Cancer Institute 

http://www.cancer.gov/newscenter/estrogenplus 

Medline Plus 

http://www.nlm.nih.gov/medlineplus/hormonereplacementtherapy.html 

National Center for Complementary and Alternative Medicine 

http://nccam.nih.gov/health/alerts/menopause 

Office of Research on Women’s Health 

Menopause Management and Hormone Therapy 

http://www4.od.nih.gov/orwh/menopause.html 

National Institute on Aging 

http://www.nia.nih.gov/health/pubs/menopause 

 vii
MENOPAUSE RELATED RESEARCH 

By Institute or Center 

 viii
 

 

 

1 

National 

Cancer 

Institute 

(NCI) 
 

 

 

2 

National Cancer Institute 

Description: 

The National Cancer Institute (NCI) supports a broad range of research related to the menopausal 

transition and cancers in women. A spreadsheet is provided describing relevant research grants 

which have been funded recently or are currently being funded by NCI. 

Search Words: menopause; perimenopause; postmenopause; hormone therapy; hormone 

replacement therapy (HRT); estrogen replacement therapy (ERT) 

The NCI provides a digest page on Menopausal Hormone Use, 

http://www.cancer.gov/clinicaltrials/digest-postmenopausal-hormone-use on the NCI website. 

The page provides a fact sheet with questions and answers on menopausal hormone use, links to 

important information throughout the National Institutes of Health, updates on recent research 

results, and links to information on current clinical trials. 

The NCI also provides information on early menopause that may occur due in women who have 

their ovaries removed before natural menopause. 

http://ovariancancer.gog199.cancer.gov/premature.html
NCI Menopause Related Grants (submitted March 2005) 

(Includes projects funded and coded through December 2004, but may not include all projects funded in F

 To search NCI grants, go to http://researchportfolio.cancer.gov/ 

Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA17054 Ross, Ronald 2005 University of 

Southern California 

Iatrogenic Causes of Cancer 

Breast Etiology/Exogenous Factors in the origin and cause of cancer; Interactions of Genes and/orGenetic Polymorphisms with Exogenous and/or Endogenous Factors 

This project is a subproject of an ongoing program project grant.: postmenopausal women has become increasingly popular since thin addition to reducing the risk of endometrial cancer associated wreduce the risk of breast cancer. It was assumed that progestogens comparable to that on the endometrium, with the results of a large of therapy widely quoted as supporting this view. However, the finwith combination oral contraceptive therapy given around the timmitotic activity peaks during the luteal phase of the menstrual cycincrease breast cancer risk in postmenopausal women. Experimeninadequate data on use of progestogen-only contraceptives. One pand breast cancer also suggests an increased risk but the number ocancer risk of combination estrogen-progestogen hormonal replacreplacement therapy, we have been conducting a large case-controcontrols indicate that unopposed estrogen therapy moderately incrdose-related fashion. The addition of a progestogen appears to enhfurther increase in breast cancer risk. We wish to expand this studeffects, the possible interaction between use of hormone replacemconfidently assess differences in risk levels with use of combinatiocancer patients are English- or Spanish-speaking women aged 55 later, and identified by our population-based tumor registry over a cases by age (+3 years), race and neighborhood of residence. A strcomprehensive manual containing color photographs of all types oin-person interviews. Validation of hormone therapy is accomplishcontrol pairs to be interviewed will allow for the evaluation of the on breast cancer risk in the presence of possible confounding variaweight, and for testing for interactions between hormone therapy abreast disease, and for careful evaluation of the effects of duration 

CA18119 Katzenellenbogen,

Benita

2009 University of Illinois

Urbana-Champaign

Antiestrogens--Mechanism ofAntagonist Action 

BreastCancer-Related Biology

DESCRIPTION (provided by applicant): Antiestrogens and SERMtamoxifen and raloxifene are the most widely used agents in the trproved to be very effective in breast cancer prevention. They are lmenopausal hormone replacement therapy as well. While it has lorequired for the actions of estrogens and SERMs, it is increasingly selectivity of SERMs are markedly influenced by coregulator prot

pattern of a remarkable number of genes through a diversity of motechnologies in an innovative two-pronged approach to understand

targeted investigation of the role of an ER-specific coregulator, REthe development of an REA knockout mouse, together with compthe action of SERMs, and (b) a global analysis of gene regulation complementary bioinformatic, molecular, and biochemical analysa clearer understanding of the gene networks through which SERMeffectiveness and tissue selectivity, and the gene-regulating activitand tumor suppressive actions in breast cancer treatment and prevselective activities for hormone replacement therapy.

3 
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA34588 Toniolo, Paolo 2002 New York 

University

New York UniversityWomen’s Health Study

BreastEndogenous Factors in the Origin and Cause of Cancer 

With this competing renewal, we seek to expand the initial observstrong association between endogenous estrogens (estrone and estparticular interest are subjects who were sampled between 5 and 1expand the cohort by 3.5 additional years to identify all subjects dthis additional effort, the cohort will be have been followed for an 1,548 incident cases of malignant tumors, including approximately 346- menopausal). Of those 124 pre- and 185 post-menopausal cablood donation. The major aim of the proposal is to examine the aestrogens (estrone, estrone sulfate, estradiol, bioavailable estradiocancer risk among subjects who samples were obtained between 0are especially eager to determine whether these associations hold associations are present in the early stages, or even before, disease whether the major androgenic precursors of estrongens (androstencancer risk in the same population. Breast cancer cases and indiviincluded in the nested case-control study and their serum samples of endogenous hormones utilizing state-of-the-art biochemical methe time of cohort enrollment (i.e., at the time of the collection of statistical analyses. 

CA40104 Haslam, Sandra 2008 Michigan State 

University

Stroma and MammaryGland Cell Proliferation 

BreastCancer-related Biology

DESCRIPTION (provided by applicant): Progestins (P) are major significantly to breast cancer risk. Since P are widely used in oral replacement therapy it is critically important that their mechanims research to delineate the mechanisms of P-dependent proliferation period, using the mouse mammary gland model, we have develop

primary culture syste

m in which mammary epithelial organoids, m

cells, proliferate and undergo alveolar morphogenesis in response mammary stroma derived-hepatocyte growth factor (HGF). Treatm

ductal morphogenesis, whereas P alone does not induce proliferatincreased apoptosis. HGF+P increase proliferation above HGF alomorphology. This is a novel in vitro demonstration of a mitogenic proliferative and alveologenesis response to P in vivo. In addition 

cells has been identified. In this proposal we will determine whethan SH3 binding domain on the progesterone receptor (PR), to affemammary-specific tublogenesis (FAK, SHIP-1, PI3-K) and prolifpromote proliferation and cause alveologenesis. We will also detetranscriptional activation function, on the expression of P-responsproliferation (

Met, cyclin D1, Myc). In addition will also identify 

myoepithelial cells) in which these effects of P occur. Using cultualso determine the role of the two PR isoforms (A and B) in prolifproposal is the delineation of the mechanisms of P-dependent growmay lead to novel strategies for the prevention and treatment of br

4 
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA46475 Colditz, Graham 2004 Brigham and 

Women's Hospital 

Benign Breast Disease and Risk of Breast Cancer 

BreastEndogenous & Exogenous Factors in the origin and cause of cancer 

DESCRIPTION: (Adapted from the Investigator's Abstract) The prisk of breast cancer experienced by women with atypical hyperplrelationship a high priority. We hypothesize that the relation betwrisk of breast cancer is stronger among women with than without areceptor activity is higher among women with atypia than among receptor is expressed by a higher proportion of women with prolifstudy using blocks from the cases and controls to assess expressiobiologic mechanisms for the progression of benign lesions to breaexpert breast histopathologists apply standard criteria. The extensicases of breast cancer and 873 controls. This will give a final data Overall, blocks will be available from 358 cases and using 2 contrDrs. Graham Colditz, Stuart Schnitt, and James Connolly have cohistopathology resource and to evaluate categories of benign chanNurses' Health Study research group provides a rich resource of inas it moves forward. This study is a key component of the Risk IdHarvard Comprehensive Cancer Center/Dana Farber Cancer Instit

CA49449 Hankinson, Susan 2009 Brigham and 

Women’s Hospital 

Biochemical Markers in the Nurses’ Health StudyCohort 

BreastColon and Rectal GastrointestinalEndogenous & Exogenous Factors in the origin and cause of cancer 

DESCRIPTION (provided by applicant): In this competing renewwork on endogenous hormones and risk of breast cancer and also addition, we propose to address a number of new hypotheses in re

in women for which few prospective evaluations of biomarkers haconduct two nested case-control studies using already collected bibreast and ovarian cancers), and both the 

Women's Health Study a

Specifically, we will evaluate plasma estrogen metabolites, prolacurinary melatonin, and urinary vs. plasma estrone sulfate, all in rethe independent contribution of endogenous sex steroids to the Gamodels. We also will evaluate plasma insulin like growth factors, progesterone receptor and vitamin D receptor in relation to ovaria282 cases in plasma analyses and 521 cases in genetic analyses (aor by far the most detailed prospective assessment of these potentiaim, we propose several pilot studies to evaluate the feasibility of 

our cohorts to identify plasma protein profiles that predict subsequcohorts, their prospective design, high follow-up rates, detailed exavailability of archived plasma, DNA and urine specimens providof public health importance. 

5 
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA58420 Rosenberg, Lynn 2009 Boston University Follow-up Study for 

Causes of Illness in Black Women 

BreastEndometrial Female Genital SystemEndogenous & Exogenous Factors in the origin and cause of cancer 

DESCRIPTION (provided by applicant): We propose to continue American women yet undertaken, the Black Women's Health Studand preventive factors for breast cancer, other cancers and importapresent grant proposal is to support continued data collection, and cohort was established in 1995 when African-American women agquestionnaires, providing data on demographic factors, medical ancontraceptives and other drugs, physical activity, smoking, diet, anevery two years by mail questionnaires that obtain information on in each cycle exceeding 80% of the original cohort. Methods for moutcomes have been established. After follow-up in the proposed available for analysis. We will prospectively assess the relation of distribution, physical activity, diet, oral contraceptive use, cigarettincidence with sufficient power to assess effects in important subgindex. We will also assess the adequacy of the Gall model for predeligibility of women for prevention trials, has never been tested in studies of some of these issues in white women, differences in risk Importantly, this proposal is not simply a repeat of studies done in relevant to black women on which data are lacking, such as the inobesity or weight gain, or of physical activity within levels of oberisk factors for breast cancer incidence. In addition, the proposed dunder another grant will provide a unique resource for assessing gillnesses in black women.

CA60050 Shapiro, Charles 1999 Ohio State 

University

Premature Ovarian Failure in Breast CancerPatients 

Bone, Osteosarcoma/Malignant Fibrous Histiocytoma, BreastPatient Care and Survivorship Issues 

Adjuvant chemotherapy reduces mortality rates in women with brprolonged survival after adjuvant treatment the long term health e

important to evaluate. Premature ovarian failure (menopause) occ

cancer patients who receive adjuvant chemotherapy. The resulting women with breast cancer may result in accelerated loss of bone, 

(osteoporosis). To investigate whether breast cancer patients who 

failure experience accelerated bone loss, in Specific Aim #1 we w

biochemical indices of skeletal homeostasis in premenopausal breinduced premature ovarian failure. In Specific Aim #2 we will tesresorption, prevents bone loss in these women. Premenopausal brwill be recruited to participate in this research study. One-hundremenstrual status, follicle-stimulating hormone (FSH), estradiol (E

questionnaire, activity questionnaire, self-rating depression questimeasurements of bone mineral density of the lumbar spine and prohomeostasis (serum ionized calcium, parathyroid hormone, and os

evaluation adjuvant chemotherapy will be administered. The base

24 months. At the 12 month evaluation women with chemotherap

participants) will be randomly allocated to either one year of nasadaily calcium intake or nasal spray placebo plus 1500 mg of oral dcontrolled trial. Tamoxifen may also prevent bone loss and inhibi

whether tamoxifen prevents bone loss in breast cancer patients wiobservational study 42 premenopausal breast cancer patients with chemotherapy and tamoxifen will undergo the baseline evaluation 

prospective studies in premenopausal women with breast cancer whemotherapy- induced ovarian failure and bone loss, and the effec

preventing the accelerated bone loss in these women. 

6 
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA63731 Buist, Diana 2005 Center for Health

Studies 

Breast CancerSurveillance in a DefinedPopulation 

BreastResources and Infrastructure Related to Cancer Control, Survivorship, and Outcomes Research Surveillance

DESCRIPTION: (Applicant's Description) This proposed project more than 100,000 women offered breast cancer screening througmammography examinations within a managed care plan (Group outcome (mortality, late-stage disease) for the target population arEnd Results reporting (SEER) registry and are linked to health carassessments). This proposal includes 3 specific aims: 1) To contina) improve data syste

m software, enhance data storage capabilitie

components pertinent to research, such as a targeted survey; and cgeneration, and data file development; 2) To use the data system thormone replacement therapy (HRT) cessation on mammographic (mammography and ultrasound) and the associated costs among wor never using HRT; C) The factors that explain the reduced sensiThe biologic and other factors that influence the likelihood of lateon stage at-diagnosis; and 3) To conduct 5 research projects relateof mammographic breast density on the 5-year risk of breast cancemenstrual cycle; c) The association between mam

mographic findi

findings"; d) The effect of computer assisted reading on mammogassociated with nodal metastases at-diagnosis among screened wocollaboration and using carefully designed prospective observatiocontribute to improvements in breast cancer screening, and the un

CA66189 ZeleniuchJacquotte, Anne 

2000 New York

University School of Medicine 

Endogenous Estrogens and Endometrial Cancer

Endometrial Female Genital Syste

m

Etiology/Exogenous Factors in the origin and cause of cancer 

This study will investigate the relation between postmenopausal edevelopment of endometrial cancer. In premenopausal women, esstimulate endometrial cell division, providing a rationale for the ropostmenopausal women, estrogen replacement therapy is associateHowever, there is no direct epidemiologic evidence that the physiobserved after menopause are positively associated with endometrof estrogen replacement therapy, to prevent cardiovascular disease endogenous estrogens may help develop prescription guidelines. frozen serum samples collected between 1985 and 1991 in a coho

of breast cancer and endogenous hormones (New York University aims of the proposal are: 1) to identify incident cases of endometrthe NYUWHS until mid-1998; 2) to conduct a case-control study incident cases of endometrial cancer are expected to occur by the 

matched on age and date of blood donation, will be selected. Con

intact uterus at time of diagnosis of the case. Infor

mation on know

interviews. Serum samples will be assayed for estrone, estradiol, p

globulin and percent free estradiol. Conditional logistic regression higher levels of endogenous estrogens are associated with a higheinvestigate whether the role of obesity in endometrial cancer can b

CA69334 McTiernan, Anne 2003 Fred Hutchinson 

Cancer Research Center 

Exercise Effect on SexHormones in Postmenopausal Women

BreastInteractions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Interventions to Prevent Cancer: PersonalBehaviors that Affect Cancer Risk 

DESCRIPTION: (Adapted from Applicant's Abstract). The primahealth goal in this country. Exercise has been associated with a devia a hormonal pathway. Exercise decreases body fat, especially awhich exercise could lower concentrations of endogenous estrogerandomized interventional study that will test the effect of a one-yandrogenous sex hormone profile in postmenopausal woman. Womrandomized to either a one-year, moderate intensity exercise progrhabits. Dietary intake will be assessed at baseline and follow-up thassayed at baseline and at end-of-study. These hormones include: bioavailable estradiol, estrone sulfate, sex hormone binding globuandrostenedione, dehydroepiandrosterone, dehydroepiandrosteronof urinary 2-hydroxyestrone (2-OHE1) to 16a-hydroxyestrone (16associated with breast cancer, will also be assayed at baseline and body mass index, total fat mass, and body fat distribution will also possible mechanisms through which exercise may be associated w

7 
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA72099 Siegler, Ilene 2002 Duke University Improving Cancer Risk 

Communication 

Bladder, Breast , Lung, Respiratory System, Urinary SystemBehavior Related to Cancer Control Education and Communication 

Major problems in cancer control are related, in part, to perceptioninclude smoking among African Americans and lack of adherence women's decisions about whether to get mammograms and take esfocus an outstanding group of Duke University investigators and a 

of cancer risk communication. Never before has there been a concommunication. Our goals are to develop a theoretical understandand test population- sensitive measures of risk perception, develop develop effective and cost-effective interventions to improve both result, we hypothesize that smoking will be reduced a

mong Africa

women in their 50's and 60's. Moreover, we will improve decision includes three projects (one in which we will use biomarkers of geamong African Americans, a study to facilitate informed decision mammography), one developmental project (to develop an improvcores (administration, biostatistics, cost-effectiveness and a risk la

intervention projects include tailored print interventions and two w

as well. All intervention-related data will be collected through tele

permit comparisons across topics and populations. There will be sthe effect of race and gender in these studies. We believe that this control by developing the next generation of state-of-the-science i

understanding of cancer risk communication. 

CA72787 Daling, Janet 2001 Fred Hutchinson 

Cancer Research Center 

Calcium Channel Blockers in Breast Cancer Etiology

Breast CancerExogenous Factors in the origins and causes of cancer 

DESCRIPTION: (Adapted from Applicant's Abstract). Although among women aged 65-79 years, little epidemiologic research has this age. Women of this age also commonly suffer from hypertens(CCBs) are often used to treat either of these conditions. Two recolder, suggest that women who use CCBs may be at an increased given biological plausibility by the observation that pharmacologiapoptosis (programmed cell death), the process whereby organisminitiated, damaged, excessive). In this sense, CCBs may be cancestudy of 1,000 women, aged 65-79, who reside in King County, WAdministration (HCFA) tapes, and who are diagnosed with their fJanuary 1, 1997 through December 31, 1999. The personal intervother known risk factors for breast cancer will be compared to a cwho will be identified through the HCFA tapes. Based on the preon cells, it is posited that the use of CCBs increases the risk of brewhether calcium antagonists used in the treatment of hypertension and cardiovascular diseases promote breast cancer in women aged channel blocker is more related to breast cancer than the other typof combined estrogen-progestin therapy in a large group of womereplacement therapy (HRT) by these women may affect the propoalso be collected and analyzed on other drugs (viz., cimetidine, anby women in this age group. 

8 
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA73638 Bolton, Judy 2006 University of Illinois 

at Chicago 

Biotransformation of Estrogen to Carcinogenic Quinoids 

Breast, Endometrial, Female Genital Syste

m

Endogenous Factors in the Origin and Cause of Cancer 

There is a clear association between excessive exposure to estroge

including breast and endometrium. The risk factors for women devestrogen exposure; early menses, late menopause, and long term e

estrogen carcinogenesis is unknown. Estrogen metabolites can act proteins or DNA. The catechol metabolites of estrogens are oxidiz

generating reactive oxygen species which can contribute to the carpreliminary data also show that the o-quinones are converted to adThe focus of this proposal is the role of quinoid metabolites in est

Establish the role of quinoids in the carcinogenic and cytotoxic efestrogens will be studied in C3H 10T1/2 cells and their ability to aThe cytotoxicity of estrogens and catechol metabolites will be invBiochemical parameters which serve as indicators of redox vs. alkthe importance of quinoid formation to the metabolism of estrogenmethide pathway to the biodegradation of estrogens will be determtheir metabolites to o-quinones will be studied. Unsaturated estrog

replacement drug, Premarin, will be investigated to probe electronestrogens to quinoids. 3. Investigate the effects of quinoid structurelectrophilicity of quinoids will be determined by measuring their examining the extent of DNA alkylation. Their redox ability will bmonitoring changes in NADPH and GSH levels in microsomal inc

examining autoxidation rates of the catechols. These data will detof estrogens and provide a basis for the development of estrogen r

CA76017 Heiss, Gerardo 2002 University of North 

Carolina Chapel Hill 

HRT and Changes in Mammographic Density

BreastExogenous Factors in the origin and cause ofcancer 

DESCRIPTION: Breast parenchymal patterns are depicted on mawhich correspond to the relative amounts of fatty tissue (c.f., epithhighest in women with the greatest proportion of epithelial, stromhigh density (>50%) has been consistently associated with significindependent of age, menopausal status, or other breast cancer risk suggested that postmenopausal HRT may increase density in some and imprecise measurement of exposure and outcomes (density) dsmall but persistent association of HRT with increased risk of breaamong postmenopausal women, assessing the magnitude and corrmay contribute to improved understanding of the aetiologic role ocancer prevention efforts. The objectives are to: 1) reliably estimdensity in postmenopausal women; and 2) determine whether HRTsince menopause, body mass, or other breast cancer risk factors. Tmulti-center, randomized trial of HRT in postmenopausal womenfor hysterectomized women, or combined progestin-estrogen for wWHI clinical centers, measurements will be made of the percentagtaken at baseline, one-year and two-year follow-up intervals, and ttreatment groups. The sample is comprised of 1200 women with African, Hispanic and Asian/Pacific Islander Americans. 

CA76366 Newcomb, Polly 2002 Fred Hutchinson

Cancer Research Center 

Hormone Replacement Therapy and Large Bowel Cancer Risk 

Colon and Rectal Cancer Gastrointestinal TractCancer-related BiologyInterventions to Prevent Cancer: PersonalBehaviors that Affect Cancer Risk 

The benefits and risks of estrogen replacement therapy continue to evidence suggests that estrogen replacement may be associated wiamong postmenopausal women. Further study of this potentially estimates of the magnitude of effect, identify salient patterns of usthis tumor in women. A population-base case-control study is propostmenopausal hormones and the occurrence of colorectal cancerwith and without progestin, the duration and currency of hormone 

Additional aims of this study are to elucidate the mechanisms of thHRT to hormone receptors and proliferation in the bowel, and to esusceptibility genes influencing the metabolism of estrogens. Ove

with 1,100 women with newly diagnosed cancer of the colon or restructured telephone interview, fixed diagnostic tissue will be obtareceptor status and proliferation markers. Blood samples on a samcontrols will be obtained for genetic studies of polymorphisms relspecifically CYP17 and the estrogen receptor gene. The proposed evidence for the degree to which HRT is protective against colorerelevant pathways for that protection. 

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CA77290 Rohan, Thomas 2006 Yeshiva University Fat Reduction, HRT Use,

and Benign Breast Disease Risk 

BreastExogenous Factors in the Origin and Cause of Cancer Surveillance

This proposed study is to evaluate the feasibility of studying womthe calcium/vitamin D supplementation (CaD) components of the HRT component) to test the hypothesis that adoption of a low-fat proliferative forms of benign breast disease. Additionally, it is profat dietary pattern, will also be associated with reduced risk. Also, analysis of risk factors for proliferative forms of benign breast disDM and CaD components of the trial. The feasibility study will ruspecific lists of eligible patients and to train clinics in the study mfor data analysis. If the proposed study is feasible, the application the etiology of the putative pre- malignant forms of benign breast prevention. 

CA77355 Helferich, William 2006 University of Illinois 

Urbana-Champaign

Dietary Isoflavone, Tamoxifen, and Tumor Growth 

BreastSystemic Therapies – Discovery and Development 

Risk of breast increases with age and the majority of breast cancer

women with breast cancer are over 50 years old. Therefore, most wwoman has E-responsive breast cancer it is likely that she is receivConsiderable research has focused on the use of hormone replacembreast cancer and most oncologists/physicians do not recom

mend 

dramatic increase in soy and estrogenic isoflavone consumption bnatural and perceived "safe" alternative to HRT. This "self-medicamenopausal and TAM-associated menopause-like symptoms is ofsafety of the dietary estrogenic isoflavones for women with E-respphytoestrogens to negate the effectiveness of TAM therapy is a po

Our preliminary results indicate that the dietary genistein, the pred

containing supplements, can negate/overwhelm the inhibitory effemice. In our proposed experiments, we will determine the minimunegate/overwhelm the inhibitory effects of TAM. Additionally, 30

equol by enteric metabolism in the large intestine. This estrogenic 

potentially increase breast cancer $sk in women (equol-producers) effective method to convert formononetin to equol for use in both allow us, for the first time, the ability to evaluate the interaction osufficient estrogenic activity to negate/overwhelm the inhibitory esummary, our studies will determine if dietary estrogenic isoflavodosages can negate/overwhelm the inhibitory effects of TAM on E

CA77398 Wright, William 2003 Public Health 

Institute

Breast and Other Cancerin the CaliforniaTeachers Cohort 

Breast CancerNutritional Science in Cancer Prevention 

A cohort of 133,000 California school teachers has been establishinvestigators with the goals of evaluating unresolved issues related important issues related to women's health. The teachers were recscanned mail survey. Scanning of the questionnaires has been comup includes routine linkage with the California Cancer Registry ancohort members for follow-up, and biennial contact for collecting on other health outcomes. The Specific Aims for this project are thypotheses related to breast cancer aetiology (specifically associatabortion/miscarriage, dietary phytoestrogens, fibre, micronutrient activities, family history of breast and other cancers, and active ancalibration/validation studies of the food-frequency questionnaire breast and other cancers reported in the baseline questionnaire; anwhich time, two or more questionnaires will be mailed to update iinformation, and assess additional disease outcomes for testing nohealth, in a timely manner. During the next five years, 2,025 invaanticipated which will provide ample statistical power to address eCalifornia Teachers Study presents a rare opportunity to study wouniformly high level of education among teachers, their experiencand geographic residences, and the relative ease with which they cintended to substantially increase knowledge of preventable risk f

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CA77530 Lydon, John 2003 Baylor College of 

Medicine 

Progesterone Receptor and Breast Cancer 

BreastCancer-related Biology

Breast cancer is recognized as the most prevalent malignancy amocurrently estimated to be one in eight. Most importantly, reproducstatus has been shown to be an important risk factor. Recently, I g

(PRKO) mouse that has demonstrated that progesterone (P), and itmammary gland proliferation and differentiation. The involvemen

controversy for several years mainly because P can protentiate or 

complex temporal relationship between P and mammary tumorigewhether the P indued-proliferative signal has a role to play in brea

function on mammary tumor progression. The specific aims of thifunction alters murine susceptibility to carcinogen-induced mammand molecular level; 2) determine whether PR function has a role 

tumors exhibited by the Grunder mouse and define whether the PR tumors to a hormone independent phenotype; and 3) to define the derived PR populations on mammary development and tumorigentransplantation technology. Apart from advancing our current und

tumorigenesis, information from these studies will aid in the desigand treatment as well as prompting a reevaluation of the current uhormonal replacement therapies. 

CA77596 Strom, Brian 2003 University of 

Pennsylvania 

Molecular Susceptibilityto Hormone Induced Cancer 

Breast, Etiology/Endogenous Factors in the origin and cause of cancer

There is strong evidence that a combination of inherited genotypeFurthermore, inherited genotypes involved in the metabolism of stdeveloping breast cancer. Knowledge about interactions of these fability to identify women at increased breast cancer risk. This knocancer prevention or treatment strategies. We propose a populatiothe complex, multi-factorial etiology of breast cancer that involvefactors. These hormonal factors include endogenous exposures meexposures to compounds such as estrogen replacement therapy (Ehypothesis. First, we will evaluate whether candidate susceptibilitcase-control analysis. The genes of primary interest will be CYP1theta genes, which are involved in the metabolism of steroid hormother reproductive risk factors interact in breast cancer etiology, aunderstanding of breast cancer etiology once hormonal risk factorwe will evaluate whether the genetic and hormonal etiology of brehypotheses, we will undertake a study in the Greater Delaware Vaa population-based sample of cases and random digit dialed controBlack subjects. Risk-factor information will be obtained from a tebe collected using a non-invasive cheek swab method. and patholomedical record abstraction. Analyses will be undertaken to evaluafactors in breast cancer etiology by race. These analyses will allow breast cancer etiology. 

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CA77617 Session, Donna 2003 Mayo Clinic 

Rochester 

Expression of Cyclin E in GynecologicMalignancies 

Female Genital Syste

m

Ovarian Cancer Cancer-related BiologyEndogenous factors in the origin and causes of cancer 

The cyclins and their catalytic partners, cyclin-dependent kineses Overexpression of cyclin genes has been described in several formthat cyclin E is expressed in a subset of gynecological cancers, namand cervix. The first specific aim will focus on confirming the speorigin. Expression of cyclin E will be assessed in different histolocervical and renal cancers. Cyclin E specificity for gynecologic clmarker to help distinguish a pelvic tumor of Mullerian versus nonimplications in cases when the primary lesion is unknown since thHistological subtype specific aberrations in cyclin/Cdk expression success of future therapies targeting Cdks. The first generation of The second specific aim will evaluate steroid hormonal regulation 

estrogen and progesterone on cyclin E activity will be assessed ussuggests a role for hormones in the etiology of gynecologic malign

regulated by estrogen and progesterone in breast cancer cell lines. reproductive tract cancer has important implications in the treatmedirection of future therapeutic and preventative agents. Specific aicyclin dependent kinase inhibitors in order to elucidate the mechacyclin/Cdk is dependent upon the association with cyclin depende

attempt to correlate cyclin E activity with the CdkIs, p2 1 and p27 estrogen and progesterone on CdkI association with cyclin E will increase cyclin E activity in breast cancer cell lines in response to the Cdk-inhibitory proteins. Understanding the mechanisms of cycaberrations may lead to powerful and convenient models for studyantiproliferative agents. 

CA77708 Greendale, Gail 2008 University of 

California, Los Angeles 

Sex Steroids &Mammographic Densityin the Postmenopause

BreastExogenous Factors in the Origin and Cause of Cancer 

 DESCRIPTION (provided by applicant): Higher mammographic and the magnitude of risk associated with mammographic density known risk factors for breast cancer. This application proposes to Density in the Postmenopause", a study of the effects of endogenopercent-density. This study is an outgrowth of the Postmenopausarandomly assigned postmenopausal women to placebo, estrogen-otreatments. To date, the principal findings of the "Sex Steroids and estrogen-only treatment did not affect mean ma

m

mographic densi

did occur in 3 groups assigned to estrogen/progestin treatments; 2estrogen-only group, the degree of increase in serum estrone level mammographic density; and 3) Endogenous (pre-treatment) serum hormone binding globulin were positively associated with baselinpropose to continue work in this study to gain a further understandspecifically: 1) What other factors are associated with baseline (pradditional factors predict increases in mammographic density duriaddition to those already studied), genetic polymorphisms in sex spolymorphisms in sex steroid receptors will be related to baseline response to treatment with hormone therapy. The proposed continUCLA and USC. Using stored samples, we will measure baseline will also extract DNA from stored samples to assess selected geneoutcome data and all relevant covariates have already been measurelations between the hormone and genetic exposures measured in as well as change in density between baseline and 12 months). 

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CA79024 Sklar, Charles 2003 Sloan-Kettering

Institute for CancerResearch 

Premature Menopause inSurvivors of Childhood Cancer 

All Cancers Patient Care and Survivorship Issues Surveillance

DESCRIPTION: (Applicant's Description) Advances in the treatm

improved survival rates. However, with these advancements, canctreatment with intensive, multimodality therapies. While the majoor recover ovarian function during or immediately after completinof these young women are at risk for premature menopause in the adult survivors of cancer diagnosed during childhood/adolescencethe development of early menopause, the impact of an early menoThe study cohort will consist of 5,500 young adult female survivoadolescence, selected from a larger population of survivors of chil(CCSS), and 3,000 sibling controls. Data will be collected using a 

following topics: menstrual history and menopause status, covariawith premature menopause, and standardized instruments which mDetailed information concerning cancer diagnosis and treatment, ifields/doses, will be known for all study participants, facilitating t

study population, the heterogeneity of diagnoses and exposures, c

assessment of interaction between the major risk factors of interes

CA80625 Cohen, Susan 2003 Yale University Menopausal Symptom 

Relief for Women with Breast Cancer

Breast CancerComplementary & Alternative Treatment Approaches Patient Care & Survivorship Issues 

The proposed randomized, placebo-controlled clinical study will esymptom management for women who experience menopause foldesigned to: 1) Test the anticipated treatment benefit for menopauseverity of hot flashes as outcome measures; 2) Explore the anticipsymptom relief using changes in severity of mood changes, sleep headache and nervousness as well as changes in luteinizing hormoquality of life; 3) Determine the feasibility of the treatment strategpreviously diagnosed and treated for breast cancer by examining rinterviews regarding the potential burden associated with symptom sessions. A three group design (site specific needling, control needwill take the form of either menopausal specific acupuncture sites the literature as irrelevant to the symptoms associated with menopThe non acupuncture control group will receive usual care with stpublished menopausal literature concerning non-hormonal menopvariables are Menopausal Symptoms with hot flashes (primary maconcentration, joint pain, headache and nervousness as measured bIndex; Physiological Measures of menopausal status (serum LH anMenopause Specific Quality of Life Questionnaire; and Protocol Dand exit interviews. A convenience sample of 81 women who expfollowing treatment for Stage I or II breast cancer will be recruitedrepeated measures ANOVA, time series analysis and content analof acupuncture as a treat

ment for menopausal hot flashes and info

controlled clinical trial of acupuncture for menopausal symptom r

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CA80636 Weiss, Noel 2001 Fred Hutchinson

Cancer Research Center 

Endometrial Cancer and CYP1A1, GSTM1 and Polymorphisms 

Endometrial Female Genital Syste

m

Endogenous Factors in the origin and cause of cancer 

DESCRIPTION: (Applicant's Description) Women who smoke cof non-smokers. Female smokers have been observed to have an increased 2-hydroxylation has been suggested as a mechanism to 

smoke. Polymorphisms in several genes involved in metabolizing 

related to an increased risk of lung cancer. One of these genes is amight be anticipated that women who have the high-risk genotypeof a condition such as endometrial cancer, whose incidence is reducase-control study, a strong, positive relationship between the presendometrial cancer risk was reported. In our proposed population

polymorphisms in some of these genes are associated with endomcytochrome P450 1A1 (CYP1A1), glutathione-S-transferases M1 methyltransferase (COMT). Cases and controls will be drawn fro

replacement therapy and endometrial cancer. Cases are women agdiagnosed between 6/l/97 and 7/31/00, who reside in western Wasrandom-digit dialing (ages 50-64 years) and Health Care Financin

in the same geographic area. In the proposed study, 175 cases and specimen at the time of interview. Using purified DNA from thesassayed using PCR and RFLPs. Differences in the distributions oassessed in the whole study population, as well as in sub-groups oof hormone replacement therapy (HRT). Since endometrial cancer could have relevance for other, more common cancers whose relaAdditionally, this information potentially could be used to predict HRT, and thus bear on a woman's decision regarding long-term us

CA80888 Carney, Patricia 2005 Dartmouth College Hormone Replacement 

Therapy and BreastCancer 

Bone, Osteosarcoma/Malignant Fibrous Histiocytoma, BreastExogenous Factors in the origin and cause ofcancer 

The long-term objective of this study is to evaluate the relationshibreast cancer detection, breast cancer risk, breast tumor prognostic Although the results of numerous case-control and follow-up studmodestly increases breast cancer risk, most studies have been unabmammographic screening. This is an important limitation because women who maintain hormone replacement prescriptions through detection of breast cancer relative to women who do not use horminvolves an existing cohort identified through the New Hampshire population-based mammography registry comprising more than 1baseline survey, administered at the time of mammography, we hainformation, including current HRT use, from all women in the NHidentified 74,200 women who are pre- or post-menopausal includifollow these women for four years prospectively to ascertain new already provided permission to link medical, radiologic and pathopurposes. We will implement a supplemental survey in Years 1 anrisk factor information and health-related quality of life. All other NHMN. Our primary specific aims are to evaluate the impact of Hand specificity of screening mammography, proportion of uninterpimaging procedures); 2) breast cancer incidence (especially combicharacteristics (e.g., TNM stage, tumor grade, axillary lymph nodconsider use of HRT to prevent osteoporosis and other diseases, uTherefore, a secondary aim is to assess the impact of HRT on healstudy will benefit radiologists who interpret mammograms, and wbalance the complex issues of disease risk and health-related qualihormone replacement therapy.

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CA81212 ZeleniuchJacquotte, Anne 2002 New York University School of 

Medicine 

Androgens and Cancer of the Endometrium 

Endometrial Female Genital SystemEndogenous Factors in the Origins and Cause of Cancer 

The hypothesis that estrogens unopposed by progesterone promot

risk of endometrial cancer, is supported by experimental as well a

source of circulating estrogens in postmenopausal women, a positendometrial cancer risk is also expected. This study will be the fir

circulating estrogens and androgens with endometrial cancer risk this project are to: (1) Assess the relation of postmenopausal endocase-control study nested within three prospective cohorts: the Ne(NYUWHS), the ORDET Study in Milan, Italy, and the Northern (2) Assess the relation of postmenopausal endogenous androgens study. For all three cohorts, serum samples collected at enrollmen

analyses. A case-control study of endometrial cancer and postmenNYUWHS and funded by the NCI (R29 CA66189, PI: A. Zeleniustudy will be implemented in the two other cohorts. All incident cIndividually-matched controls will be selected among all subjects 

characteristics: postmenopausal at entry, alive, free of cancer and case, and matching the case on age at enrollment (+6 months), and for the NYUWHS participants, data on potential confounders will and ORDET participants. Serum samples of all cases and matched estradiol, free-estradiol, estrange, testosterone, androstenedione, Dcohorts will result in a total of 140 cases, a much larger number th

CA81220 Johnson, Christine 2005 Case Western 

Reserve Univ-HenryFord Health Sciences Center 

Colon Cancer Survivors--Medications & Risk of Recurrence 

Colon and Rectal Gastrointestinal TractPatient Care and Survivorship Issues 

Colorectal cancer will be diagnosed in over 129,000 Americans in decrease the risk of colorectal cancer, such as chemoprevention, ainflammatory drugs (NSAIDs) and hormone replacement therapy cancer. Little is known of their effect on persons with a history of expanding population as survival has been significantly improving epidemiologic study is to determine whether NSAIDs or HRT is aindividuals diagnosed with colorectal cancer. The proposed researtreated with curative intent and create a comprehensive longitudinsubsequent adenomatous polyps, colorectal cancer and survival. Tuse deceases the risk of recurrence of colorectal cancer; (2) to deterecurrence of colorectal cancer; (3) to determine whether NSAID whether HRT use affects short-term survival. The cohort will be etwo managed care organizations, Health Alliance Plan (Detroit, Msubjects will be followed for at least five years for new evidence oautomated pharmacy data, the timing of use and exposure to NSAsurvivors, along with potentially confounding variables, in relation 

CA81243 Spink, David 2003 Wadsworth Center Carcinogenicity of B

Ring Unsaturated Estrogens 

BreastCancer-Related BiologyEndogenous Factors in the Origin and Cause of Cancer 

The major concern regarding estrogen replacement therapy (ERT) that accompanies long-term use. The most commonly used formulargely of B-ring unsaturated estrogens including conjugated formstudies show Ah-receptor-regulated metabolism of Eqn to 4-hydrocell lines expressing cytochrome P4501B1 (CYP1Bl). Semiquinometabolites, which are adductive and lead to free radical productiohypothesize that estrogens are involved in both the initiation and paromaticity of the B-ring of steroidal estrogens increases carcinogdetermine whether steroidal estrogens, including the B-ring unsatumetabolic activation via catechol estrogens. 0ur Specific Aims arseries of immortalized tumor- and non-tumor-derived human brea

involving hydrolysis of conjugates, reduction to 17beta-dihydro fohydroxyation to catechol estrogens will be investigated. 2) Determcytochromes P450 of the CYP1, CYP2, and CYP3 families with Eas substrates. 3) Establish transgenic mouse lines expressing humthe effects of treatment with Eq and Eqn on DNA damage and the CYP1B1-transgenic mice. The studies described here will providunsaturated estrogens by human enzymes in breast epithelial cellsof metabolic activation of Eq, Eqn, and endogenous in the initiatio

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CA85913 Daling, Janet 2005 Fred Hutchinson 

Cancer Research Center 

HRT Use and Risk of Lobular and Ductal Breast Cancer

Breast CancerCancer-Related BiologyExogenous Factors in the Origin and Cause of Cancer 

Incidence rates of invasive lobular breast carcinomas (ILBC) have whereas the trend of increasing incidence of ductal breast cancer hhas occurred specifically among women over age 50. The use of ctherapy (CHRT) has also risen steadily over this time period, and suggest that postmenopausal women who use CHRT may have an relationship of CHRT to ductal cancer. Few epidemiologic studies for breast cancer differ across different histologic types, but such ibe multiple pathways leading to the development and progression The primary objectives of this proposed study are to confirm recenlobular breast cancer in a large population-based study, to assess tmechanisms for this association. We propose to conduct a case-codiagnosed with breast cancer (450 lobular, 450 ductal) and 450 poSeattle-Puget Sound metropolitan area of western Washington. Thof CHRT associated with an increase in the incidence of invasive use of CHRT associated with an increase in the incidence of invasthe duration, patterns and/or recency of CHRT use influence he size of the association? the histologic characteristics, tumor cell proliferation, or expressiocycle and cell death regulator proteins of lobular and ductal breast 

CA87538 Rossing, Mary 2007 Fred Hutchinson

Cancer Research Center 

Epidemiology of OvarianCancer: New Hypotheses 

Female Genital SystemOvarian Exogenous Factors in the Origin and Cause of Cancer 

Much of the previous epidemiologic research on ovarian cancer haconceptual framework of the ovulation and gonadotropin. Howevefor epidemiologic findings regarding this disease. In this study, we risk of epithelial ovarian cancer. We will examine the relation of ehormone replacement therapy (HRT) with disease risk. We will fuvitamin D influence risk. The study will contribute to a better undovarian cancer, and may provide information leading to new meanpropose to conduct a population-based, case-control study of epithresiding in thirteen counties of Washington State. Cases will be idoperating as part of the Surveillance, Epidemiology and End Resurandom digit telephone dialing, and will be selected to be similar iinterviews will be conducted and blood samples will be collected. 

health importance. Study of the impact of different HRT regimensovarian cancer risk has been deemed an urgent task for research. Runopposed estrogen and combined estrogen/progestin HRT highlimedications with ovarian cancer risk, and to incorporate this know

CA87969 Colditz, Graham 2004 Brigham And 

Women's Hospital 

Dietary and Hormonal Determinants of Cancerin Women 

Breast CancerColon and Rectal CancerGastrointestinal TractGenital System, FemaleOvarian Cancer 

 Using repeated measures of exposure and the long follow-up in thseries of analyses relating specific aspects of diet, nutritional statuand survival among women with breast cancer. DNA samples from between functional important polymorphisms and risk of breast caexposures will also be related to tumor characteristics using pathobreast cancer cases. Dietary hypotheses include that low folate intparticular tumors characterized by negative estrogen receptor statureceptor and p16; that dietary fiber and specific types and sources conjugated linoleic acid (CLA), and decreases in adiposity each reglycemic load and intakes of heterocyclic amines from cooked meperiod) total fat each in increase risk. Polymorphisms in genes relmanganese SOD, and NAT1/2) will be examined in relation to brecorresponding dietary factors. We also propose to evaluate the typin relation to overall risk of breast cancer and estrogen receptor stof dietary fat reduces survival among women with breast cancer, band avoidance of weight gain each increase survival. Because of texposure, long follow-up, and large numbers of breast cancer caseanalyses will provide important data for women and their health p

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CA89393 Iglehart, James 2005 Dana-Farber Cancer 

Institute

Plasma estrogens in breast cancer risk and prevention

BreastChemoprevention Technology and/or Marker Evaluation with Respect to Fundamental Parameters of Method Technology and/or Marker Testing in a Clinical Setting

 A large body of epidemiologic evidence has consistently linked rmenarche and first pregnancy are parameters in established breast replacement therapy also increase postmenopausal breast cancer rbeing widely prescribed to reduce breast cancer risk/8. This is due identify those women who most benefit from tamoxifen. We and o

estrogens are highly correlated with breast cancer risk 9,10. Strateprominent a

mong the various therapeutic hormonal interventions u

postmenopausal women, adjuvant chemical or surgical oophorecto

women, agents that inhibit aromatase, the critical enzyme in convein the circulation, breast tissue, and tumors 12. Currently available substantially reduce circulating estrogen levels without altering otin the treatment of metastatic disease, and a large adjuvant trial is breast cancer prevention by translating these observation into clinthat by incorporating data on serum estrogen levels and mammogrimprove current models of individual breast cancer risk. In the seccancer prevention among postmenopausal women at increased risk whether an aromatase inhibitor is sufficiently well tolerated (by itblood lipids) to permit further development for chemoprevention. adoption of quantitative paradigm of breast cancer risk estimation accepted models of cholesterol and blood pressure titration that ha

CA89552 Habel, Laurel 2006 Kaiser Foundation 

Research Institute

Mammographic Denisityin a Multi-Ethnic Cohort 

BreastExogenous Factors in the Origin and Cause of Cancer 

Mammographic density is one of the strongest known risk factors the most undervalued and underutilized factors in studies of breasinterest in the potential value of mammographic density as an intequestions remain unanswered. A needed area of research is the iderelated to mammographic density, and may therefore act through a feature. The aim of this study is to identify factors that are associaon race/ethnicity, circulating hormones (e.g., estradiol, progesteromineral density, and modifiable factors such as diet (e.g., phytoest(e.g., recreational activity, occupational activity, and household acwomen transition through the menopause. This proposal seeks funapproximately 178 Chinese, 209 Japanese, 102 African-American(Study of Women's Health Across the Nation). We will request alduring the SWAN follow-up period and request that women have six. SWAN is a multi-site population-based study designed to inveethnicities. At baseline and six annual follow-up exams, data are canthropometry, bone mineral density, menstrual information (e.g.histories. In addition, blood is drawn, timed to the luteal phase of in assessing mammographic density will measure total area of the and classify mammograms according to parenchymal pattern (Womerged with data from SWAN to create analytic files. Repeated mthe association between factors of interest and mammographic denopportunity to efficiently examine the relationship between severacancer and mammographic density. The results will improve our uand help determine whether mammographic density should be concancer risk for intervention studies of several modifiable factors. 

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CA89617 Pollard, Jeffrey 2005 Yeshiva University Progesterone, Cell Cycle 

and Cancer

BreastEndometrial Female Genital Syste

m

Endogenous Factors in the Origin and Cause of Cancer 

Estrogens are the major carcinogen in the environ

ment of most fem

the risk of breast and endometrial cancer. Conversely, it has becomfor the well being of women (and men) throughout life. Progesteroproliferation and, consequently, it is used in the treatment of endohormone replacement therapy designed to alleviate post-menopaufundamental importance to understand the mechanism of action of ovariectomized mice, a single injection of estradiol-17beta (E2) reand cell proliferation that is restricted to the uterine epithelium. Thpretreatment with progesterone (P4). The uterine epithelium can bbiochemical analysis. This method together with defined hormonastudy the mechanism of action of these hormones in vivo. In tissuactivation of cyclins and their dependent kinases (Cdk). These incacting early in G1 and the cyclin E-Cdk2 complex acting at the Gepithelium have shown that E2 induces the re-localization of cycli

activation of cyclin-E and cyclin ACdk-2 activities and hyper-photreatment prohibited the cyclin D1/Cdk-4 relocalization to the nucphosphorylation. In addition, P4 abrogated the E2 induced cyclin 

this grant are: 1) To determine the mechanism whereby P4 prohibtreatment; 2) To determine the mechanism of action of P4-inhibitiregulated genes in the uterine epithelium following E2 treatment imethods to interfere with signaling pathways in the uterine epithelthat the mechanisms of cyclin D1/Cdk4 exclusion can be identifieisolated. Furthermore, novel E2 and P4-regulated genes that play iproliferation should be identified. These studies will define speciftherapeutics that would inhibit estrogen's mitogenic effects in tumendometrial polyps and endometriosis. 

CA89750 ZeleniuchJacquotte, Anne 2003 New York University School of 

Medicine 

Serum Lignan and Risk of Endometrial Cancer

Endometrial Female Genital Syste

m

Exogenous Factors in the Origin and Cause of Cancer 

There is strong experimental and epidemiologic evidence that estrendometrial women. Because of their anti-estrogenic properties (thsynthesis) and possible tumor growth inhibition properties, it has bhormone-related cancers, in particular breast and endometrial cancserum levels of the main human ligand, enterolactone, are negativstudy will use the resource of an ongoing case-control study of enestrogens, nested within 3 cohorts, the New York University WomStates, the Northern Sweden Health and Disease Study (NSHDS) Italy. This ongoing study is funded by NIH. Case subjects are all iappropriate parent study dates. Two controls matching the case on (+/-6 months), and date of enrollment (+/-3 months) will be selectsamples (for the NYU WHS and the ORDET Study) or plasma samenrollment in the cohort, and stored at 300 C are available for biocFinland by Dr. Adlercreutz, who developed, the assay methodologeligible for the study. The availability of this ongoing study offers rapidly and at a minimal cost. 

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CA90440 Gupta, Chanda 2006 University of 

Pittsburgh atPittsburgh

Role of Estrogens in Development of LungCancer 

LungEndogenous and Exogenous Factors in the Origin and Cause of Cancer 

This project is a sub-project of the SPORE in Lung Cancer (PI: Swomen are more susceptible to lung cancer than men, suggesting Estrogens are known to act as tumor promoters, through a receptoare some reports of estrogen receptor expression in lung tumors, aorgan. Recent findings that early menopause is associated with a rreplacement therapy results in an increased incidence of lung canc

this hypothesis comes from our recent studies, which identified malpha, and in some cases ERbeta, in non- small cell lung tumor cefrom the lung. Estrogen induced increased cell growth in lung tumanti-estrogen ICI 182,780. Estrogen also enhanced growth of the lTamoxifen, an inhibitor of estrogen, reduced the in vivo growth opresence of estrogen, suggesting tamoxifen may be a partial agonithese findings, we hypothesize that estrogen plays a direct role in mechanism and may be responsible for at least some of the increa

may also help explain the high proportion of women among non- PROJECT One of this SPORE application found that expression ogene was associated with a diagnosis of lung cancer in non-smoki

by estrogen in lung cells expressing the ERbeta. This suggests a mIn Project Two of the SPORE, we will examine the role of estrogethe frequency and level of expression of the ERalpha and ERbeta ability of estrogens to enhance tumor cell proliferation in vitro and effect; (3) determine relative mRNA expression levels of the ERs neoplastic histology from current and former smokers; (4) determimportant in lung cancer proliferation; and (5) examine in on-goinone, whether estrogens influence lung cancer risk.

CA90579 Boyd, Norman 2003 Ontario Cancer

Institute

Effects of Diet on Growth Hormone-IGF-1 Axis

BreastNutritional Science in Cancer Prevention 

The specific aim of this proposal is to determine whether In premeInsulin like Growth Factor-I, Insulin like Growth Factor Binding Plow-fat high- carbohydrate diet. The general method to be employhormone on blood samples, and nutrient analysis of food records, multicentre randomized dietary intervention trial. This trial is desilow-fat high-carbohydrate diet will, in women with extensive mamincidence of breast cancer by 29 percent. The trial is explanatory ieffect of dietary fat reduction in terms of a reduction in breast canparticipants highly motivated subjects who are at increased risk of level of assistance in making a dietary alteration, we follow them and the correct identification of subjects who develop breast cancestudy group and dietary compliance. Recruitment of the 4615 subj1998. (A total of 4693 were randomized). Blood samples and food to test the hypotheses given below about the effects of dietary intewith breast cancer risk. Modulation of these factors by dietary intewhich diet may influence risk of breast cancer. Although not the pnature of the trial, the complete follow-up of all subjects, and the cultimately allow any changes in blood markers found in the presenbreast cancer incidence. 

19
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA91019 Ross, Ronald 2006 University of 

Southern California 

Genes and the Estrogen Effect on Endometrial Cancer 

Endometrium Female Genital Syste

m

Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors 

The etiology of endometrial cancer is relatively well understood. Emodulatory effects of progestins is the major cause. Estrogen replthe principal risk factors. The effect of the latter is probably due to circulating bioavailable estrogen levels. Oral contraceptives and pto the endometrium but with the continuous modulatory influence Combination hormone replacement therapy in which a progestin iresults in no increase in endometrial cancer risk over that of a nonERT and obesity are the major risk factors, only a small proportiowill develop endometrial cancer. It would be important from a pubable to predict which women those will be. We propose to evaluat

HSD17B1, ER, CYP1A1, CYP1B1, COMT andPR) in the estrogepathways to determine if the effects of these risk factors might be evaluate this question in the context of a prospective epidemiologi

California Teachers Study) using a nested case-control design. We phytoestrogens on endometrial cancer risk reduction in conjunctio

under evaluation. 

CA93772 Sillman, Rebecca 2006 Boston Medical 

Center 

Breast Cancer Treatment Effectiveness in OlderWomen

BreastPatient Care and Survivorship Issues 

 DESCRIPTION (provided by investigator): An estimated 192,20more than half of whom were 60 years of age or older. Of concern have declined among women less than 70 years old, they are eitheolds) among those 70 years or older. One explanation for this is thmore frequently than younger women. Neither efficacy nor effectiadvantage of the Health Maintenance Organization (HMO) Cancehistorical cohort study of an unselected group of older women (>6breast cancer (stages I-II) between 1990 and 1994. Specifically, wprimary tumor therapy (breast conserving surgery, axillary dissectmastectomy) versus other than standard therapy in preventing breamorbidity, tumor characteristics, geographic site, and demographiaddition of systemic adjuvant therapy (chemotherapy, hormonal thhormonal therapy) modifies the effectiveness of standard and othebreast cancer recurrences and mortality; (3) Describe patterns of sdetermine the extent to which surveillance testing is associated wi(4) Identify provider, tumor, and patient characteristics associated and systemic adjuvant therapy in older women with newly diagnofrom throughout the United States will together identify and follow medical record data sources will be used to collect information thaeffects of treatment, tumor, and patient characteristics on breast castudy will inform clinical practice, particularly the care of older wparticipate in clinical trials. 

20
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA94745 Rossing, Mary 2004 Fred Hutchinson

Cancer Research Center 

Use of Antidepressants and Risk of Breast Cancer 

BreastExogenous Factors in the Origin and Cause of Cancer 

Diagnosis of depression is increasing in the United States, and wodepressive symptoms. With the advent of the selective serotonin rincreased dramatically during the 1980s and 1990s, and the types evidence that antidepressants can reduce the occurrence of menopantidepressant use may increase still further, particularly among wtherapy due to concerns about breast cancer risk. Thus, better undbreast cancer etiology is of substantial and growing public health antidepressants in human carcinogenesis was sparked by reports o

administered tricyclic antidepressants or SSRIs. Epidemiologic fin

this concern. Two recent studies reported an elevated risk of breashowever, the class or type of antidepressant associated with increapotential for error in self-reported drug use, and by relatively smal

a population-based, case control study to examine the association within the Group Health Cooperative of Puget Sound (GHC). App

breast cancer (3,080 with invasive disease) during 1990-2000 and included. Antidepressant use will be ascertained through the GHC confounding factors will be obtained from risk factor surveys rout

broad, recent interval of diagnosis years of cases will allow examiantidepressants overall, classes of drugs (e.g., SSRIs or tricyclics)

paroxetine. Use of the pharmacy database will provide unbiased a

based on self-reported drug use. 

CA95113 Modugno, 

Francesmary

2004 University of 

Pittsburgh atPittsburgh

Serum Markers ofBreast/Ovarian Cancer Risk 

BreastOvarian Female Genital Syste

m

Endogenous and Exogenous Factors in the Origin and Cause of Cancer 

Both breast and ovarian cancers are costly in terms of morbidity asome well-defined behavioral risk factors, there are few, if any, espaucity of markers that have the possibility to be applied in a clinicollected data and serum samples available to researchers to exploprospective setting, are urgently needed in order to identify womeimprove our models of risk assessment and to devise effective preinstitutional consortium linked to an ongoing multi-center trial in biomarkers as risk factors for breast and ovarian cancers. In particserum markers of estrogen metabolism, body mass index (B

MI), a

postmenopausal breast cancer risk; and (2). determine prospectiveon postmenopausal ovarian cancer risk. To achieve our objectiveswithin the Observational Study (OS) of the Women?s Health Initiwomen?s health funded by the NIH. The first study will compare banked serum between 200 confirmed cases of invasive breast canage, race and study site. The second study will compare insulin, gbanked serum between 200 confirmed cases of epithelial ovarian cage, race, study site and HRT status. Risk factor, confounding and by the WHI Clinical Coordinating Center and will be provided to be performed by experienced, collaborating investigators with whstudies comes from preliminary data we have generated. Approvaobtained from the WHI. By the end of this project, we will have pmarkers of risk for breast and ovarian cancer. We also expect to idanticipate studying further in a multi-center, collaborative fashion 

21
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA95717 Porter, Peggy 2006 Fred Hutchinson

Cancer Research Center 

Molecular Alterations in Lobular/Ductal Breast Cancer 

BreastExogenous Factors in the Origin and Cause of Cancer 

Lobular breast cancers differ both morphologically and clinically steroid hormone receptor expression and proliferation rates. Breas

may also be distinct with respect to allelic loss patterns and compoand BRCA1/BRCA2-mediated DNA repair. It has been difficult to most studies can only evaluate a small number of this relative uncinvasive lobular and ductal breast cancer will be collected and test

part of an NCI-funded case-control study to assess associations be

therapy (CHRT) and the incidence of both invasive lobular and du

tissue samples collected in the study, we propose to 1) evaluate thand protein over-expression in 350 each of invasive lobular and dugenome- wide rate of allelic loss in 100 each of lobular and ductal 

(HuSNP). The large amount of data that is being carefully collectethe contribution of alterations in BRCA-related DNA repair compphenotypes such as ER and PR positive or negative subgroups. Th

and ductal cancers will provide the most comprehensive descriptio

about morphology-specific traits gained from studying a large numunderstanding of the biology of distinct subsets of breast cancer, pstratification into prognostic and treatment groups and/or inform ttumor types. 

CA97475 Lampe, Johanna W 2004 Fred Hutchinson 

Cancer Research Center 

Hormone Status Postmenopause: Colonic Bacterial Effects 

Breast Cancer Prevention/ Hormone Exposure Endogenous Factors in the Origin and Cause of Cancer Resources and Infrastructure Related to Biology

DESCRIPTION (provided by applicant) Greater exposure to estroof developing breast cancer. In the gut, microflora play a significainter-individual differences in host bacterial populations may be a breast cancer risk. Colonic microfloral production of equol from thunique intestinal bacterial population. Evidence from several studwith the capacity to produce equol have hormonal profiles associathird of individuals have the yet-to-be-identified bacteria capable determined readily from a urine sample collected after a 3-day soy study of the effect of equol producer phenotype on estrogen-depenassociation between equol producer phenotype and current and lifCirculating reproductive hormones and urinary estrogen metabolitevaluate current hormonal exposure. Breast and bone densities (

m

by equol producer phenotype. We will recruit healthy female voluwomen who participated in the Physical Activity and Total Health Hormones in Postmenopausal Women). Women in this study had density by computer-assisted technology, total bone density measuanalysis of circulating reproductive hormones, and a urine sample Thus, by using this study population, we make efficient use of a cbone density, and circulating and urinary hormone data. Each womthe first-void urine on the fourth day for analysis of equol. We wiland will examine differences in percent breast density by equol prwhether equot production predicts differences in the measures of hknown to be associated with these measures. The results of this stuof the equol-producer phenotype, a marker of colonic nticrofloral 

22
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA98741 CampbellThompson, Martha 

2005 University of Florida Alternative Estrogen

Replacement Therapy forColon Cancer 

Colon and Rectal CancerGastrointestinal TractComplementary and Alternative Prevention Approaches 

 DESCRIPTION (provided by applicant): Botanical products are bestrogen replacement therapy (ERT). Clinical evidence strongly suof colon cancer in postmenopausal women. After follow-up of wotherapy, the Women's Health Initiative recently reported a 37% reon placebo. In another 20 published studies, half support an inversreduction in risk. Despite these findings, few investigations are unpreventive effect is achieved. Estrogenic effects are mediated by bthe second estrogen receptor subtype, ERbeta, is the subtype foun

reduced expression of ERbeta mRNA in colon tumors compared tfollowing over-expression of ERbeta, human colon cancer cells diindependent growth. These data imply that ERbeta could mediate hypothesis being tested is that alternative ERT based on phytoestrcolon carcinogensis. Specific aims are proposed to test the followi

human colon cancer cells will decrease tumorigenic phenotype in in mice) by interference of EGFR signaling pathways, and (2) A pinduced aberrant crypt foci by decreasing proliferative activity in to define how activation of ERbeta-mediated responses can modu

clover extract with ERbeta-selectivity can decrease carcinogen inichemopreventive effect on colon cancer development and the mecexpand our understanding of colon cancer and provide a new theraalternative ERT inhibits the adenoma-carcinoma sequence could acancer recurrence in female patients, as well as developing better women. The clinical translational potential of this hypothesis lies respond to phytoestrogens. These results would also suggest additon selective estrogen receptor (ERbeta) therapies.

CA99491 Assaf, Annlouise 2003 Memorial Hospital 

of Rhode Island 

The Effect of EtOH and Folate on Hormone Related Cancers 

BreastEndometrial Female Genital Syste

m

Ovarian Exogenous Factors in the Origin and Cause of Cancer 

The heavy, regular use of alcohol has been associated with signifimenopausal women. The consumption of high levels of alcohol haendometrial, and ovarian cancer. The risks associated with low to This may be due to differences in hormone replacement therapy oaccurately assessing level of drinking. We hypothesize that high lelikelihood of developing breast, endometrial, and ovarian cancer aalcohol on these cancers. Design: The Women's Health Initiative Omenopausal women who were enrolled between September 1993 ubeen 1,999 incident cases of breast cancer, 253 cases of endometrwomen enrolled in this study. Data regarding the use of alcohol, dwas collected on each participant at baseline and again at a followanalysis of the effect of alcohol consumption and folic acid intake cancers. Conclusions: Breast cancer now ranks second in cancer dcause of morbidity. While the incidence of endometrial cancer is nrates are low, endometrial cancer resulted in over 6,500 deaths in associated with a very high mortality rate (approximately 50% for stage. The Women's Health Initiative database provides a unique ofolic acid intake with hormone-related cancers in post-menopausa

CP 10128 Brinton, Louise 2003 National Cancer 

Institute

Breast cancer detection demonstration project follow-up study - I

BreastOvaryColon Endogenous and Exogenous Factors in the Origin and Cause of Cancer 

This study follows about 60,000 women who were former participDetection Demonstration Project (BCDDP), a nationwide breast cThe follow-up started in 1980, with ascertainment of cancer and mFollow-up Study is particularly valuable for ascertaining the risks therapy associated with cancers of the breast and colon. Analyses between hormone replacement therapy and benign breast disease a

to use of replacement hormones. Research efforts also have focusedensities in relation to subsequent breast cancer risk and the relatiat various ages, and use of certain medications to breast cancer risBreast Cancer Detection Demonstration Project, a nationwide breaestrogen-only replacement therapy, particularly for ten or more yeovarian cancer. Women who used short-term estrogen-progestin-but risk associated with short-term and longer-term estrogen-proginvestigation. 

23
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

NR05084 Avis, Nancy 2006 

Wake Forest University Health Sciences 

Acupuncture Treatment for Menopausal Hot Flashes

BreastComplementary and Alternative Treatment Approaches Patient Care and Survivorship Issues 

 DESCRIPTION (provided by applicant) Hot flashes and/or night associated with menopause. For many women these symptoms can and interfere with daily activity. They often occur at night, waking fatigue and depressed mood. Relief from hot flashes and night swwomen initiate hormone therapy (HT). Hot flashes are a particular breast cancer. Currently, the gold standard for treatment of vasomassociated with a number of risks and is often contraindicated for have had breast cancer. Given the risks and side effects associated treatments for hot flashes. Unfortunately, many of these treatmentshown to be effective. Modern theories of neurophysiologic and nTraditional Chinese Medicine (TCM) suggest that acupuncture maflashes. A few small pilot studies, as well as clinical practice, have effective treatment. The goal of this R21 pilot grant is to demonstrtrial to test the effectiveness of acupuncture for treating menopausplan to seek R01 funding to conduct a fully powered randomized tassigned to one of 3 groups: (1) standardized acupuncture with vacare. Our primary outcome will be a reduction in hot flash frequenimprovement in sleep, mood, and overall quality of life. The purptreatment and the placebo acupuncture protocols and to demonstrathe study. The study is organized with Wake Forest University ScCoordinating Center and Massachusetts General Hospital (

MGH) 

(UNC) serving as the clinical sites. The specific aims of this pilot protocols, (2) to determine the feasibility of conducting the proposretaining subjects throughout the study, (3) to obtain preliminary dfrequency and severity, as well as to obtain data on these outcomeand (4) to assess our ability to track program costs associated with participants. 

CA104852 ZeleniuchJacquotte, Anne 

2008 New York

University School of Medicine 

Endogenous Estrogens and Colorectal Cancer Risk in Women

Colon and Rectal CancerGastrointestinal TractEndogenous Factors in the Origin and Cause of Cancer 

 DESCRIPTION (provided by applicant): The evidence from epidassociated with a decreased risk of colorectal cancer (CRC) has beobservation of a statistically significant reduction in risk of CRC iplacebo-controlled, clinical trial. Despite the evidence on the protedevelopment, there are no epidemiologic studies to date on the asspropose to test the hypothesis that postmenopausal serum levels owith subsequent risk of CRC in a case-control study nested within (NYUWHS) cohort. Between 1985 and 1991, the NYUWHS enrofollowed up ever since. Serum samples collected at time of enrollmtotal of 227 cases of colorectal adenocarcinoma are expected to be 

postmenopausal at entry, and these cases will be included in the pselected who match the case on age at, and date of, enrollment, ansamples from cases and matched controls will be retrieved and assandrostenedione, testosterone, and SHBG. Data on potential confo

the first study on the association of postmenopausal circulating esNYUWHS is particularly well suited to study the proposed hypothminimizes the risk for bias and allows to examine pre-diagnostic hsex hormones in the development of diseases has always been its p

24
Grant # Principal 

Investigator

Last

Year 

Active

Institution Project 

Title 

Cancer Site/ Area of Research 

Abstract

CA110797 Modugno, 

Francesmary

2006 University of 

Pittsburgh

The Role of Prolactin in Postmenopausal Breast Cancer

BreastEndogenous Factors in the Origin and Cause of Cancer 

 DESCRIPTION (provided by applicant): Laboratory data suggestdevelopment and lactation, may also play a role in breast carcinogmainly case-control studies with extremely small sample sizes. OnStudy) has examined the question, noting a significant positive assmagnitude to that of estrogen and breast cancer. If validated, these research into the development of chemopreventive agents, similar prevention. Thus, a large prospective study is urgently needed. Thevaluate the extent to which PRL levels are related to breast cancethe following hypothesis: Among postmenopausal women, serum cancer risk. We will further evaluate the effects of sex steroid hormcancer association. As a secondary aim, we will explore the relatiobreast cancer, including tumor stage, grade and ER/PR status. We Osteoporotic Fractures (SOF). SOF is a prospective study that col9704 postmenopausal women in the United States. Since 1986, 48enrollment. We will measure prolactin levels in the prospectively-cancer during follow-up and 375 SOF participants who did not derelationship between prolactin and breast cancer, we will use Cox age, family history, age at first birth, age at menarche, age at menoparity, ever breast fed, and history of benign breast disease, as weour study will support the development of breast cancer chemopreApproval for this study has already been obtained from SOF and w

CA113023 Dorgan, Joanne 2005 Fox Chase Cancer 

Center 

Pilot Study of Adrenal Hormones 

BreastExogenous Factors in the Origin and Cause of Cancer 

DESCRIPTION (provided by applicant): Breast Cancer is a hormshown that postmenopausal women with elevated serum levels of of developing breast cancer. Of particular interest, postmenopausa

dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), are apcompared to those with lower levels. In the proposed pilot study, wfor a revised R01 application to prospectively determine if increassteroidogenesis pathway is responsible for increased adrenal androcancer. Specific aims for the proposed pilot study are: 1) quantify serum pregnenolone, 17OH-pregnenolone, progesterone, 17OH-pdetermine if a single measurement of pregnenolone, 17OH-pregne

and 11-deoxycortisol adequately reflects longer-term levels. For awomen who donate blood to the Fox Chase Biosample Repository batches. Coefficients of variation and intraclass correlation coefficreproducibility. For aim 2, hormones will be measured in serum c

donated serum to the Columbia, MO Serum Bank. Intraclass corre

whether hormone measurements in a single aliquot reflect longer t

25
 

26 
 

National 

Eye 

Institute 

(NEI) 

27 
 

28 

National Eye Institute

FY 2004 Menopause Related Research 

The National Eye Institute (NEI) supports menopause related research in the following areas: 

• Dry eye: Lacrimal insufficiencies affect roughly two million Americans, particularly 

post-menopausal women. NEI-supported researchers are investigating the hypothesis 

that lacrimal insufficiency is triggered by loss of hormonal support for the lacrimal 

gland's secretory capacity. Much of the dry eye disease that afflicts women after 

menopause 

• The role of estrogen in the etiology of glaucoma and cataract 

• Antioxidant effects of estrogen in age-related macular degeneration: 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY011239-08 

Program Director: FISHER, RICHARD S 

Principal Investigator: AGRE, PETER C MD INTERNAL MED 

Title: Aquarporin Water Channel Proteins in Eye 

Institution: JOHNS HOPKINS UNIVERSITY BALTIMORE, MD 

Project Period: 1996/02/01-2006/06/30 

DESCRIPTION: (provided by applicant): Numerous physiological and pathophysiological processes 

involve the transport of water across cell membranes. The molecular identity of water transporters 

became known with discovery of the aquaporin family of membrane water channels. Four of the ten 

known mammalian aquaporins are expressed in anterior segment of eye. This application addresses the 

molecular mechanisms regulating function of human AQPO, AQP1, AQP3, and AQP5 and dysfunction 

of these proteins in clinical disorders of eye. Aim I. Analysis of aquaporin proteins in normal human eye. 

New reagents will be prepared including plasmids encoding wild-type, site-directed mutant, and epitopetagged human AQPO, AQP1, AQP3, and AQP5. Antibodies specific for the N- and C-termini of the 

human proteins will be raised in rabbits and affinity-purified. The biophysical functions of human 

aquaporins will be expressed in Xenopus laevis oocytes and analyzed at baseline and after activation. 

Human aquaporins will be expressed in yeast and purified for reconstitution into proteoliposomes for 

permeation studies, into planar bilayers for analysis of electrophysiological properties, and into membrane 

crystals for structural studies. The distribution of these aquaporins will be defined in normal human eye. 

Aim II. Analysis of aquaporin proteins in clinical disorders of eye. The distribution of human aquaporins 

will be defined in tissues from patients with cataract or Sjogren's syndrome. Basic mechanisms by which 

AQPO and AQP5 may contribute to these disorders will be sought including defects in water and solute 

permeation, membrane trafficking, subunit oligomerization, and internalization, Physiological deficits 

will also be evaluated in rodent models of AQPO degradation and AQP5 deficiency. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 
 

29 

Grant: 5R01EY014847-02 

Program Director: FISHER, RICHARD S 

Principal Investigator: ARGUESO, PABLO PHD 

Title: O-Glycans on Mucins at the Ocular Surface 

Institution: SCHEPENS EYE RESEARCH INSTITUTE BOSTON, MA 

Project Period: 2003/09/01-2008/08/31 

 DESCRIPTION (provided by applicant): Mucins are a family of large and heavily O-glycosylated 

glycoproteins synthesized by all wet-surfaced epithelia, including the corneal and conjunctival epithelia. 

The ocular surface epithelia produce the secreted mucin MUC5AC and the membrane-associated mucins 

MUC's 1, 4 and 16. Terminal carbohydrates on mucins are the most exposed to the extracellular milieu, 

but little is known about their roles and character in each mucin at the ocular surface. Our previous 

studies have demonstrated that binding of an antibody specific to a terminal carbohydrate on MUC16 is 

altered in dry eye patients. This proposal is aimed at identifying terminal carbohydrate structures on 

individual ocular mucins, the enzymes involved in their biosynthesis and the role of terminal O-glycans in 

maintaining a wet ocular surface and preventing pathogen invasion. AIM I: We hypothesize that 

individual mucins are differentially O-glycosylated by the ocular surface epithelia. We propose to: A. 

Characterize the repertoire of terminal O-linked carbohydrates on individual mucins isolated from tears of 

normal individuals. B. Identify and localize glycosyltransferases (sialyltransferases) responsible for their 

biosynthesis. C. Test in vitro the role of terminal O-linked carbohydrates on mucins of the glycocalyx in 

conferring disadhesive properties to epithelial cells and resistance to transfection with adeno-associated 

viruses. AIM II: We hypothesize that in dry eye patients there is an alteration in terminal O-glycan 

structures of the membrane-associated mucins that affects hydration of the ocular surface. We propose to: 

A. Determine if there is an alteration of terminal carbohydrates of each membrane-associated mucin 

purified from the apical tear surface of dry eye patients. B. Determine if there is an alteration in the 

expression of glycosyltransferases (sialyltransferases) in dry eye patients. C. Determine in vitro whether 

the depletion of terminal carbohydrates on mucins in corneal and conjunctival cells enhances the 

penetrance of rose bengal into these cells. AIM III: We hypothesize that O-linked carbohydrates present 

on the secreted mucin MUC5AC in the tear fluid have specific affinity to P. aeruginosa, preventing their 

attachment to the ocular surface glycocalyx and facilitating their clearance. We propose to: A. Compare 

the binding of P. aeruginosa to the O-linked carbohydrates of individual mucins collected from tears. B. 

Determine in vitro how inhibition of O-glycan synthesis on membrane-associated mucins affects P. 

aeruginosa adherence to corneal cells. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R41EY015991-01 

Program Director: HELMSEN, RALPH J 

Principal Investigator: BENNETT, GREGORY MD 

Title: Nanoliter Tear Osmometer for the Detection of Dry Eye 
 

30 

Institution: OPTICOLOGY, INC. NEW YORK, NY 

Project Period: 2004/09/30-2005/03/31 

This research intends to develop a Nanoliter Tear Osmometer for the detection of the presence and degree 

of dry eye. It is estimated that 40-60 million Americans have dry eye symptoms. Prescription 

pharmaceuticals are appearing on the market to treat dry eye yet methods for diagnosis and monitoring 

treatment remain problematic. This Phase I research will make use of a new technology for analyzing tear 

osmolarity, which is popularly accepted by experts in the field as an indicator of the occurrence and 

severity of dry eye. Specifically, the research will develop an instrument to analyze nanoliter volumes of 

tears that offers quick, reliable, and an accurate measure of osmolarity. It is the intention of research team 

to develop a system that is simple to use and requires no special training thereby making it a suitable 

device for the clinical ophthalmologist or optometrist. The technological approach proposed is unique and 

innovative, as it overcomes many of the shortcomings of conventional osmolarity measurements. 

Commercial potential for such a device is high, since it is projected that cost in production will be in-line 

with other instruments purchased by clinicians. The pharmaceutical industry has invested large dollar 

amounts into treatment of dry eye and expect large returns in the next several years. With this 

introduciton of prescription treatment of dry eye it may become a necessity to have proper a diagnostic 

tool, and the osmometer proposed has attributes ideally suited for clinical examinations. The use of 

existing proven technology and applying it to tear osmolarity forms the basis of this Phase I research. 

Several factors on the effectiveness of measuring tear osmolarity will be examined, including resolution, 

sensitivity, and overall performance. The research will conclude with an IRB approved study.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R01EY015304-01 

Program Director: LIBERMAN, ELLEN S 

Principal Investigator: BERNSTEIN, STEVEN L MD OPHTHALMOLOGY 

Title: A functional approach to treating optic nerve stroke 

Institution: UNIVERSITY OF MARYLAND BALT PROF SCHOOL 

 BALTIMORE, MD 

Project Period: 2004/08/01-2007/05/31 

 DESCRIPTION (provided by applicant): Isolated axonal strokes comprise more than 3/4ths of the 

166,000 strokes that occur in the US every year, but until now there has been no in-vivo model to analyze 

this stroke form. We have developed a new rodent anterior ischemic optic neuropathy (rAION) model of 

CNS axonal stroke that directly correlates with human AION. We have characterized the response of the 

neurons and optic nerve following axonal stroke. We have determined that rAlON results in optic nerve 

demyelination and loss of function. We have also found that estrogen significantly reduces the loss of 

neurons following rAION. We hypothesize that: 1) axon ischemia-associated demyelination blocks optic 

nerve repair. 2) Estrogen enhances post-stroke optic nerve recovery. Our proposal is designed to answer 

three related questions: 1) What RGC axonal transport and glial changes occur in-vivo following rAION, 

contributing to permanent optic nerve damage? To answer this question, we will use the rAION model to 

define early retina and optic nerve stress-related cellular events, and identify the time course of optic 
 

31 

nerve demyelination and remodeling resulting from optic nerve stroke. This work will be performed using 

histological, electrophysiological, and molecular methods. 2) Can reducing post-stroke demyelination 

increase post-stroke function? With the rAION model, we will use anti-demyelinating drugs, to determine 

whether reducing post-stroke demyelination decreases permanent optic nerve damage and increases 

function. This work will be performed using electrophysiological, stereotactic retrograde tracing, 

molecular, and histological methods. 3) Does estrogen also exert neuroprotective effects when 

administered after optic nerve insult? With the rAION model, estrogen and estrogen inhibitors, 

electrophysiological, histological, stereotactic, and molecular methods, we will determine the effect of 

differences in dose, timing, sex, and blockade of endogenous estrogen. Our experimental results obtained 

with this model will enable rational design of clinically effective, neuroprotective strategies that can 

minimize ischemic axonal stroke damage. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R01EY015857-01 

Program Director: FISHER, RICHARD S 

Principal Investigator: CANDIA, OSCAR A 

Title: Fluid Movement across Conjunctiva: Stimulation and Reg. 

Institution: MOUNT SINAI SCHOOL OF MEDICINE OF NYU NEW YORK, NY 

Project Period: 2004/09/01-2008/08/31 

DESCRIPTION (provided by applicant): We have previously characterized the isolated rabbit 

conjunctiva as an epithelial model of Na absorption and CI secretion. Our hypothesis was that these 

transport mechanisms, by providing the driving forces for fluid movement across the tissue, could enable 

the conjunctiva to either absorb fluid from, or contribute fluid to, the aqueous layer of the tear film. This 

was demonstrated with direct experiments using the rabbit epithelium. Our current hypothesis is that the 

human conjunctiva may also possess transporters that enable it to absorb Na and secrete CI with the 

consequent fluid absorption or secretion. For this fluid flow to occur, the conjunctiva must have (as most 

fluid transporting epithelia do) water channels, which are usually different in the apical and basolateral 

domains. We thus propose to identify with biochemical and histochemical protocols, the electrolyte 

transporters and water channels (aquaporins) in the human conjunctiva relevant towards the movement of 

fluid flow across the epithelium. Because receptor-mediated responses are atypical in rabbit conjunctiva, 

assays similar to those in human will be done on murine and porcine tissues to determine the best model 

for fluid transport in the human conjunctiva. Since aquaporins (AQPs) play a crucial role in fluid 

transport, and our experiments have shown that anisotonic conditions and cAMP-elevating agents can 

modify water permeability, protocols to understand the regulation of water permeability in murine and 

porcine tissues will be implemented. Biochemical, histochemical and functional experiments will be 

conducted on mice, rat and pig conjunctivae. From the determination of the transporters, the AQPs, and 

the functional physiological experiments that can be done on the conjunctiva of the selected animal 

models, a theoretical model for the fluid movement across the human conjunctiva will be proposed. From 

these studies we expect to expand the understanding of the physiology of the mammalian conjunctival 

epithelium, and provide evidence that direct or receptor-mediated stimulation of ionic transport 

mechanisms will result in fluid secretion towards the tear film. These studies may provide the 

groundwork for the design of future treatment modalities for dry-eye syndromes.

Date Run: 03/16/05 PUBLIC ABSTRACTS 
 

32 

Grant: 5U10EY013626-03 

Program Director: KURINIJ, NATALIE 

Principal Investigator: COLEMAN, ANNE L MD 

Title: Incidence of late macular degeneration in older women 

Institution: UNIV. OF CALIFORNIA LOS ANGELES LOS ANGELES, CA 

Project Period: 2002/08/15-2007/07/31 

DESCRIPTION: (Applicant's Abstract) Age-related macular degeneration is the number one cause of 

irreversible blindness in the United States and is more prevalent in older, Caucasian women. Although 

there have been several studies on the incidence of ARM, none of these studies has been able to provide 

accurate estimates on the incidence of late ARM and/or the progression of ARM in the oldest old, those 

individuals over 80 years of age, because of the limited sample sizes in these studies in this age group. 

The population in the Study of Osteoporotic Fractures (SOF) is an appropriate cohort in which to evaluate 

the incidence of late ARM and the progression of ARM, because the mean age of the women at the reexamination will be 84.4 years of age and the sample is mainly Caucasian. The proposed research study 

aims to determine the incidence of late ARM, the rate of progression of ARM, and the association of 

specific risk factors such as diabetes mellitus and prior cataract surgery with late ARM and the 

progression of ARM in elderly women. In addition, it aims to determine the trajectory of visual decline in 

older women over a 14- year period. Secondarily, it aims to determine the impact of late ARM on visiontargeted health-related quality of life and to determine whether or not an association exists between the 

progression of ARM and the risk of falling and hip/non-spine fractures. In 1997 to 1998 (Visit 6), 5482 

women had an eye examination that consisted of a medical and ocular history, nine questions from the 

National Eye Institute Visual Function Questionnaire (NEI-VFQ), and measurements of visual acuity, 

contrast sensitivity, peripheral vision with automated perimetry, intraocular pressure, and uncorrected 

refractive error. These women also had a refraction and imaging of their lenses and fundi of both eyes 

through dilated pupils. Approximately 4.5% of these women have photographically validated late ARM, 

41.5% have early ARM, and 54% have no ARM or hard drusen only. In the proposed re-examination, we 

will update their medical and ocular history and ask them the nine questions from the NEIVFQ. In 

addition, visual acuity and contrast sensitivity will be re-measured. Fundus photographs of both eyes 

through dilated pupils will be obtained. These photographs and the relevant photographs from 1997 to 

1998 will be graded for ARM with the Wisconsin Age-Related Maculopathy Grading System 

(WARMGS) in a masked fashion so that the readers do not know which film is from which visit. The 

University of Wisconsin will also grade the fundus photographs on 30% of the eyes with ARM and 10% 

of the total sample. This will allow the identification of women in SOF who have had progression of their 

ARM and developed late ARM since 1997 and 1998. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 2R01EY012245-05 

Program Director: HUNTER, CHYREN 

Principal Investigator: CORTOPASSI, GINO A 

Title: Mitochondrial Mechanisms in Optic Neuropathy 

Institution: UNIVERSITY OF CALIFORNIA DAVIS DAVIS, CA 
 

33 

Project Period: 2000/05/01-2009/04/30 

DESCRIPTION (provided by applicant): Our long-term objective is to clarify the mitochondrial 

pathogenetic mechanisms of both Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic 

Atrophy (DOA), which eventually causes optic neurodegeneration as a result of two distinct 

mitochondrial causes, defects in which may be integrated into a common pathophysiological pathway. 

Our microarray analyses have supported an alternative mechanism for LHON, and thus our Aims have 

been focused in that direction. Firstly, we propose to confirm the altered expression of 'gene leads’by RTPCR and Western and Elisa, and to assay the effects of LHON mutations on secretion and cell migration 

in LHON and DOA cell models. Secondly we will test alterations in Complex 1, and of mitochondrial 

structure. Thirdly, we will dissect the source of altered mitochondrial Ca 2+ signaling in LHON models. 

Fourthly, we will attempt to create new cellular LHON models to strongly test the hypotheses, and to test 

possible homologies between LHON and DOA by microarray. Lastly, we will begin to test mechanismbased compounds, and to also begin random screening of compounds, for anti-LHON and anti-DOA 

effects.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY006177-20 

Program Director: FISHER, RICHARD S 

Principal Investigator: DARTT, DARLENE A PHD 

Title: Mechanism of Lacrimal Gland Secretion 

Institution: SCHEPENS EYE RESEARCH INSTITUTE BOSTON, MA 

Project Period: 1985/06/01-2006/05/31 

DESCRIPTION (provided by applicant): A decrease in secretion or an alteration in the composition of 

lacrimal gland fluid is a primary cause of the ocular surface problems that occur in aqueous tear-deficient 

dry eye resulting from lacrimal gland disease, contact lens wear, LASIK surgery, and aging. 

Parasympathetic and sympathetic nerves are well-known stimuli of lacrimal gland secretion and the 

signaling pathways activated by these stimuli have been characterized. A new type of stimulus of lacrimal 

gland secretion, epidermal growth factor (EGF), has been identified. Based on this finding, the following 

working model has been proposed for the present grant: Activation of sensory nerves from the ocular 

surface stimulates parasymapthetic and sympathetic nerves that innervate the lacrimal gland to release 

their neurotransmitters. These neurotransmitters activate specific signaling pathways to stimulate the 

synthesis of EGF and cause its release by ectodomain shedding from the basolateral membranes. The 

released EGF interacts with EGF (erbB) receptors on the lacrimal gland acinar cells activating a signaling 

pathway that causes secretion of proteins including the shedding of EGF family members from the apical 

membranes. These growth factors are released into lacrimal gland fluid to protect the ocular surface. The 

long term goal of the experiments described in this proposal is to test this model. From the results of the 

proposed study, new treatments for dry eye, based on stimulating EGF-, cholinergic, and alpha1-

adrenergic-dependent signaling pathways to induce secretion, could be developed. To reach this goal the 

following specific aims have been proposed: 1) Which EGF receptor subtypes participate in stimulation 

of lacrimal gland secretion?; 2) Which cellular signaling pathways does EGF activate to stimulate 

lacrimal gland protein secretion?; and 3) How are the expression and release of EGF, transforming growth 

factor (TGF) alpha, and other EGF family members regulated? Acini will be prepared from rat lacrimal 

glands. Immunoprecipitation, Western blot analysis, immunofluorescence microscopy, and EGF receptor 

deficient mice will be used to determine if EGF activates and alpha1-adrenergic agonists transactivate 
 

34 

EGF receptors to stimulate secretion. Biochemical assays, inhibitors, and adenovirus transduction will be 

used to determine the cellular signaling pathways activated by EGF compared to cholinergic and alpha1-

adrenergic agonists. lmmunofluorescence microscopy, Western and Northern blot analysis, and RT-PCR 

will be used to determine how the expression and release of EGF and its family members is regulated. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R03EY014627-01S1 

Program Director: LIBERMAN, ELLEN S 

Principal Investigator: DYNLACHT, JOSEPH R PHD 

Title: Effect of Estrogen on Radiation-induced Cataractogenesis 

Institution: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS 

 INDIANAPOLIS, IN 

Project Period: 2003/09/30-2006/08/31 

Abstract Text Not Available

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R03EY014627-02 

Program Director: LIBERMAN, ELLEN S 

Principal Investigator: DYNLACHT, JOSEPH R PHD 

Title: Effect of Estrogen on Radiation-induced Cataractogenesis 

Institution: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS 

 INDIANAPOLIS, IN 

Project Period: 2003/09/30-2006/08/31 

DESCRIPTION (provided by applicant): The induction of cataracts is often an unfortunate and 

unavoidable consequence of conventional radiation therapy for head and neck or ocular tumors, wholebrain irradiation, and total-body irradiation prior to autologous bone marrow transplantation. Though not 

life-threatening, radiation-induced cataractogenesis represents a potentially serious sequelae of 

radiotherapy which can require surgical intervention. While the cellular and molecular mechanism(s) of 

radiation-induced cataractogenesis have not been clearly elucidated, damage to the genome at the time of 

exposure and subsequent proliferation of the radiosensitive cells in the germinative zone of the lens 

epithelium likely play a role in the process. Using a rat model, we have recently accumulated preliminary 

data which indicate that estrogen reduces the latent period and may increase the incidence and severity of 

radiation-induced cataracts. High estrogen levels are artificially induced in nonpregnant women using 

oral contraceptives, or in post-menopausal women on estrogen replacement therapy, and these groups 

may be at an increased risk for developing cataracts which are more severe or occur with a more rapid 

onset. Estrogens regulate several proteins involved in cell cycle control and apoptosis, and its metabolism 

results in the production of free radicals which may be genotoxic and mutagenic to mammalian cells. 

Thus, a novel hypothesis to be tested in the proposed studies is that estrogen alters cell cycle regulation, 

DNA double strand break induction or repair, and proliferation in irradiated lens cells. We shall also 
 

35 

investigate the dose-time interactions of radiation and estradiol to better understand the mechanism of 

estrogen action, and we will determine whether estrogen-modulation of radiation cataractogenesis is 

estrogen receptor (ER)-mediated using knockout mice that are deficient in either ERalpha or ERbeta. The 

lens has frequently been used as a model for predicting delayed (late) effects in other irradiated tissues. 

Data obtained from the proposed study may demonstrate that the lens is a useful model for predicting late 

effects in other estrogen-responsive target tissues. Finally, the efficacy of utilizing a novel technique for 

small animal irradiations shall also be tested; in this study, using the Leksell Gamma Knife, only one eye 

shall be irradiated in each of the animals, with the contralateral eye serving as a control.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY014594-02 

Program Director: LIBERMAN, ELLEN S 

Principal Investigator: EISNER, ALVIN PHD 

Title: Female Hormones and Vision 

Institution: OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND, OR 

Project Period: 2003/04/01-2007/02/28 

DESCRIPTION (provided by applicant): The long-term goal is to elucidate the roles that female 

hormones have on the eye and vision. The information gained is expected to provide quantitative means 

of assessing duration-dependent effects of medications that affect estrogen receptors or that alter estrogen 

levels. The clinical emphasis will be on 2 types of medications - selective estrogen receptor modulators 

(SERMS) and aromatase inhibitors. Both are used as adjuvant therapy for early-stage breast cancer, or are 

likely to be used for this purpose or for breast cancer prophylaxis. SERMS can act either as estrogen 

agonists or antagonists depending on the target tissue. Aromatase inhibitors block the production of 

estrogen. The main objective is to identify the functional and anatomical changes that occur in the eye and 

visual system as a result of estrogen-receptor action and to elucidate the effects of 2 SERMS, tamoxifen 

and raloxifene, as functions of their durations of use. Because tamoxifen has long been the medication of 

choice for adjuvant breast cancer therapy and has been shown to affect the eye and vision, it will serve as 

the focus. In this way, potential side effects of newer medications can be compared against those of the 

standard of care. The main use of raloxifene at present is to prevent osteoporosis. The aromatase inhibitor 

to be evaluated, anastrozole, currently is used for treating advanced breast cancer. There are 4 specific 

aims: (1) To define the changes of visual function that occur during the 5-year period of tamoxifen use. A 

longitudinal design will be used to test 2 hypotheses: a) that tamoxifen alters the adaptation properties of 

SWS-cone pathways in the visual-field periphery, and b) that 2 distinct tamoxifen-user response groups 

can be defined on the basis of visual changes that occur after several years. Psychophysical measures will 

be compared with results of automated perimetry. (2) To determine the time course of tamoxifen-induced 

changes of ocular anatomy. A longitudinal design will be used to test the hypothesis that the retinal nerve 

fiber layer often thickens during year 1 of tamoxifen use but later thins. Anatomical measures will be 

made using the Heidelberg Retina Tomograph and the Zeiss Ocular Coherence Tomograher. (3) To 

distinguish the effects of raloxifene and anastrozole from those of tamoxifen. The same techniques will be 

used as for Specific Aims 1 and 2. (4) To determine the prevalence of cyclic changes of SWS-conemediated sensitivity across the menstrual cycle. Data from healthy women who are identified as having 

large cyclic sensitivity changes will be obtained from high and low estrogen-response portions of the 

menstrual cycle, and the visual changes that occur over weeks will be used to help interpret effects of 

prolonged exposure to SERMS.
 

36 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY014477-02 

Program Director: MARIANI, ANDREW P 

Principal Investigator: ELLIOT, SHARON J PHD 

Title: ECM Regulation by Estrogen in ARMD 

Institution: UNIVERSITY OF MIAMI-MEDICAL CORAL GABLES, FL 

Project Period: 2003/07/01-2007/06/30 

DESCRIPTION (provided by applicant): Age-related macular degeneration (ARMD) is the most 

important cause of lost central vision in the elderly. Although ARMD pathogenesis is unknown, oxidant 

injury to the RPE has been implicated as a mechanism. Since oxidant-mediated cellular injury leads to 

dysregulation of extracellular matrix (ECM) turnover by injured cells in many age-related degenerative 

disorders, this may also be the case for injured RPE. Additionally, dysregulated MMP-2 and its major 

substrate type IV collagen, may be induced in injured RPE to promote ARMD progression by 

macrophage-derived oxidants, myeloperoxidase (MPO), as well as macrophage-derived cytokines, 

especially tumor necrosis factor-alpha (TNF-alpha). Alternatively, estrogens, which are natural 

antioxidants and modulators of the molecules involved in ECM turnover, might oppose the injurious 

effects of macrophage-derived oxidants and cytokines on RPE production of MMP-2 or collagen. Based 

on preliminary data, we postulate that macrophage-derived MPO injures the RPE cell membrane to 

induce bleb formation but with simultaneous down-regulation of MMP-2 (leading to trapping of the blebs 

as subRPE BLD). Subsequent RPE exposure to macrophage-derived TNF-alpha, during a vulnerable 

post-blebbing period, will stimulate increased MMP-2 and collagen expression. Conversely, we expect 

that estrogen's antioxidant action on the cell membrane will diminish MPO-induced blebbing and that 

activation of estrogen receptors will modify matrix molecule dysregulation.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY003306-26 

Program Director: FISHER, RICHARD S 

Principal Investigator: GIPSON, ILENE K. 

Title: MUCINS OF THE OCULAR SURFACE 

Institution: SCHEPENS EYE RESEARCH INSTITUTE BOSTON, MA 

Project Period: 1979/08/01-2005/07/31 

The mucus of the tear film is responsible for maintenance of fluid on the surface of the eye and for 

providing a microbe barrier to protect the eye from infection. Ocular surface diseases such as those of the 

dry eye type, vitamin A deficiency, ocular surface infections as well as allergic conjunctivits may involve 

mucus deficiency, disruption of the mucus layer, or discharge of large amounts of mucus. During the 

previous funding period, we demonstrated that three mucin genes are expressed by the ocular surface 

epithelium, two prevalent ones being the membrane- spanning mucin MUC4 and the goblet cell-specific 

mucin MUC5AC. We sequenced portions of MUC4 and developed probes, antibodies, and assay methods 

for both mucins that we now propose to use in four specific aims toward understanding aspects of the 
 

37 

function and regulation of expression of these mucins on the ocular surface in normal and pathologic 

states. Aim I: Characterize two aspects of the membrane-spanning mucin MUC4 on the ocular surface. A. 

determine whether the mucin remains associated with the apical membrane glycocalyx or whether its 

extracellular domain is shed into the tear film. b. Test candidate inducers of MUC4 gene expression, 

based on presence of putative transcription factor binding sites identified from sequencing the MUC4 

regulatory region and on preliminary data indicating their potential role in its regulation. Aim II: We 

hypothesize that conjunctival goblet cell differentiation is characterized by induction of expression of the 

MUC5AC gene and that such induction can be regulated by environmental stimuli as well as cellular 

effectors. We propose to: a. determine in a mouse model whether goblet cell differentiation/Muc5AC 

expression can be influenced by surface irritants, infections, or specific allergens; b. determine whether 

conjunctival goblet cell differentiation can be enhanced in vitro, based on demonstrated presence of 

regulatory elements in the promoter region of MUC5AC and on culture conditions known to affect 

gastrointestinal goblet cell differentiation. Aim III: Determine if MUC5AC has specific affinities for 

MUC4 and the bactericidal proteins prevalent in the tear film, lysozyme, and secretory IgA. Aim IV: 

Determine in a specific type of dry eye (Sjogren's syndrome), and in seasonal allergic conjunctivitis 

whether amounts of MUC4 and MUC5AC mRNA and protein differ from the normal population. We 

hypothesize that dry eye syndromes are characterized by loss of surface wetting due to reduced amounts 

of MUC5AC and MUC4 protein, whereas, allergic conjunctivitis is characterized by an increased amount 

of mucins to facilitate allergen removal. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY011224-09 

Program Director: FISHER, RICHARD S 

Principal Investigator: GLASGOW, BEN J MD 

Title: PROTEINS IN MOLECULAR MECHANISMS OF TEAR FILM 

FORMATION 

Institution: UNIV. OF CALIFORNIA LOS ANGELES LOS ANGELES, CA 

Project Period: 1996/02/01-2006/01/31 

DESCRIPTION (Adapted from applicant's abstract): The tear film is composed of a complex mixture of 

protein, lipid and mucin components that lubricate and protect the human ocular surface. The long term 

objective of this application is to understand better the molecular mechanisms of the protein components 

in human tears. This application focuses on the structure-function relationships of tear lipocalin (TL), the 

principal lipid binding protein in tears. The knowledge of the requirements and mechanisms of the normal 

components of the tear film will be useful in achieving the ultimate goal of treating dry eye diseases. The 

experimental approach takes advantage of a combination of recent methods for monitoring lipid binding 

and elucidating protein structure including electron paramagnetic resonance (EPR), site directed spin 

labeling, and site-directed tryptophan fluorescence (SDTF). SDTF was recently developed in this 

laboratory and involves the sequential replacement of amino acids with tryptophan to provide information 

about solution structure and backbone motion of proteins with a real-time resolution in the nanosecond 

range. This application is designed to capitalize on and advance this technology in accomplishing the 

following Specific Aims: 1) To test the hypothesis that tear lipocalin scavenges and solubilizes lipids 

from the corneal surface; 2) To investigate the molecular mechanisms of lipid binding in tear lipocalin. 

The hypothesis that tryptophan 17 and isoleucine 98 contribute to strand interactions to form a 

hydrophobic cluster for lipid binding will be tested. 3) To determine the secondary structure of the D, E, 
 

38 

and F strands of tear lipocalin in solution; 4) To determine structural configurations that confer ligand 

specificity. The hypothesis that the loop between the E and F strands acts as a pH dependent gate for 

ligand access to the lipid binding core of tear lipocalin will be tested. In order to design logical treatment 

strategies including pharmacological solutions for dry eye disease, it is imperative to understand the 

molecular mechanisms involved in the normal function of tear film components. This project is 

anticipated to contribute to this understanding. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 2R01EY011386-08 

Program Director: FISHER, RICHARD S 

Principal Investigator: HAMM-ALVAREZ, SARAH F PHD 

Title: Microtubule-based transport in lacrimal gland function 

Institution: UNIV. OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 1996/07/01-2009/03/31 

DESCRIPTION (provided by applicant): A major contribution to ocular morbidity is lacrimal 

dysfunction, affecting over 10 million Americans, primarily women. At least two to four million cases are 

autoimmune-mediated and accompanied by additional symptoms, which lead to the diagnosis of Sjogren's 

syndrome. Development of primary lacrimal deficiency and Sjogren's syndrome are associated with 

changes in hormonal status and also environmental and genetic factors. Although the precise mechanisms 

involved in disease development remain unclear, these diseases are associated with impaired release of 

secretory products into ocular surface fluid by the lacrimal gland. The principal cell of the lacrimal gland 

and primary contributor of proteins into ocular fluid is the lacrimal acinar cell. Disease-related changes in 

release of secretory products into ocular fluid imply, at some level, changes in the molecular mechanisms 

responsible for exocytosis at the apical plasma membrane of lacrimal acini. Our approach to the study of 

diseases affecting lacrimal gland secretory functions has therefore focused on elucidating the mechanisms 

responsible for accurate exocytotic release of secretory pro- ducts at the apical plasma membrane of 

healthy lacrimal acini, and to determine how changes in these mechanisms are related to the establishment 

and progression of lacrimal disease. Findings during the previous project period have defined the 

involvement of several key effectors of exocytosis including rab3D, vesicle-associated membrane protein 

2, cytoplasmic dynein and actin filaments. Moreover, compensatory retrieval of acinar apical plasma 

membrane, essential for regeneration of secretory vesicles, utilizes a unique clathrin-mediated endocytotic 

mechanism involving actin, syndapins and N-WASP. Key questions regarding other fundamental 

mechanisms of lacrimal acinar exocytotic pathways remain unanswered, and will be addressed in Aims 

#1 and #2 using reconstituted primary rabbit lacrimal acini as an experimental model. To begin to address 

the changes in exocytotic pathways associated with initiation and progression of Sjogren's syndrome, Aim 

#3 probes age- and sex-related changes in organization and composition of the exocytotic pathway in 

lacrimal glands from control BALB/c mice as well as NOD mice, an experimental model of Sjogren's 

syndrome. Technically, these aims utilize an array of techniques including light and electron microscopy, 

biochemical analysis of subcellular membranes and proteomics. The specific aims are: Aim #1. Do 

lacrimal acinar cells contain distinct secretory vesicle populations? Aim #2. How do actin filaments 

facilitate exocytosis of secretory vesicles in lacrimal acinar cells? Aim #3. What components of the 

exocytotic pathway undergo age-related changes in lacrimal glands from BALB/c and NOD mice?
 

39 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R01EY011386-08S1 

Program Director: FISHER, RICHARD S 

Principal Investigator: HAMM-ALVAREZ, SARAH F PHD 

Title: Microtubule-based transport in lacrimal gland function 

Institution: UNIV. OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 1996/07/01-2009/03/31 

Abstract Text Not Available

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY009611-09 

Program Director: KURINIJ, NATALIE 

Principal Investigator: HANKINSON, SUSAN E MPH EPIDEMIOLOGY 

Title: PROSPECTIVE STUDY OF RISK FACTORS FOR EYE DISEASE 

Institution: BRIGHAM AND WOMEN'S HOSPITAL BOSTON, MA 

Project Period: 1995/01/01-2005/12/31 

We propose to investigate several lifestyle and genetic factors in relation to age-related macular 

degeneration (AMD) and primary open angle glaucoma (POAG) in two prospectively followed cohorts of 

women and men. Specifically, we will evaluate dietary intake of antioxidants and fat (including specific 

types of fat), postmenopausal hormone use and variants in the ATP-binding cassette-transporter retina 

(ABCR) gene in relation to both wet and dry AMD, and antioxidant intake, smoking, and systemic blood 

pressure in relation to POAG. The Nurses’Health Study (NHS) began in 1976 among 121,700 women 

ages 30-55 at that time. About 89,000 participants completed an extensively validated semiquantitative 

food frequency questionnaire (FFQ) in 1980 and every 2-4 years since. The Health Professionals Followup Study (HPFS) began in 1986 among 52,000 men ages 45-75, all of whom completed a FFQ at baseline 

and every four years since. Both groups have been sent a questionnaire biennially to update exposure 

information and reports of major illnesses, including AMD and POAG. Information has been collected 

repeatedly on specific vitamin supplement use, smoking, diagnosis of hypertension, reported blood 

pressure, and postmenopausal hormone use among other factors. Over 32,000 blood samples were 

collected in the NHS in 1989-90 and over 18,000 in the HPFS in 1993. In the proposed study we will 

confirm reports of AMD and POAG by contacting the participant's ophthalmologist, and obtaining 

detailed information from the optical record, including fundus photographs for those with AMD. A case 

will be considered to have AMD if it is judged to be sufficient to result in a visual acuity loss of at least 

20/30 and is confirmed by a standardized review of the fundus photograph; wet and dry types will be 

carefully delineated by photographic review. A case will be considered to have POAG if confirmed by 

medical record review and is documented to have visual field loss. We anticipate 554 cases of exudative 

and 833 cases of dry AMD, and 1049 cases of POAG. Stratified and multivariate techniques will be used 

to quantify the risk of AMD and POAG according to the level of exposure after controlling for potentially 

important confounders; analyses will be conducted among participants who reported having a recent eye 

exam. Overall, the prospective design, large size of the cohorts, the high follow-up rates, repeated 
 

40 

exposure measures, and carefully confirmed disease definitions provide a unique opportunity to evaluate 

several hypotheses of public health importance. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R03EY014021-03 

Program Director: FISHER, RICHARD S 

Principal Investigator: JACOB, JEAN T PHD 

Title: Capillary Electrophoresis Profiling of Tears in Dry Eye 

Institution: LOUISIANA STATE UNIV HSC NEW ORLEANS NEW ORLEANS, LA 

Project Period: 2002/05/01-2006/04/30 

DESCRIPTION: (Applicant's Abstract) We propose to investigate and develop an inexpensive and 

reliable method to determine the lipid and protein composition of tears that could be used both in the 

basic science laboratory and clinically in a diagnostic laboratory setting. Our approach would not only 

generate the detailed information needed for more precise diagnosis of dry eye conditions, but also 

provide the basis for development of more specific and effective categories for (and possibly therapies 

targeted directly to) the individual deficiencies that ’characterize the spectrum of dry eye disorders. More 

than 12 million people in the United States alone have been clinically diagnosed with some form of 

keratitis sicca or dry eyes. Although their symptoms are similar, the underlying causes are often unknown 

and no practical methodology for evaluating the composition of tears from such patients exists. To date, 

analysis of tear composition has been hampered by the minute sample sizes available and the technical 

inability to identify and measure the components of such a complex fluid at concentration scales of 

nanomoles or less. Capillary electrophoresis-electrospray ionization mass spectrometry (CE-ESI/MS) is a 

sensitive, relatively inexpensive method capable of analyzing samples 2 pl or less in size. Using micellar 

electrokinetic capillary chromatography techniques coupled with mass spectrometry detection, we plan to 

design and develop 1) a novel standard separation method for the lipids within tears and 2) a novel 

standard separation method for the proteins within tears. We will then investigate the use of these 

methods to develop standard lipid and protein component profiles of normal tears and identify specific 

component differences in the tears from two different dry eye models. The development of this 

technology to provide specific information on the complex disorder know as dry eye could provide relief 

to and enhance the quality of life of millions of patients for whom no reliable long-lasting therapy is 

currently available. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY010736-08 

Program Director: FISHER, RICHARD S 

Principal Investigator: JUMBLATT, MARCIA M 

Title: Conjunctival Mucins:Synthesis and Function 

Institution: UNIVERSITY OF LOUISVILLE LOUISVILLE, KY 

Project Period: 1996/05/01-2005/08/31 

Abstract Text Not Available
 

41 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY014102-04 

Program Director: FISHER, RICHARD S 

Principal Investigator: LANG, RICHARD A PHD 

Title: Molecular Regulation of Lacrimal Gland Branching 

Institution: CHILDREN'S HOSPITAL MED CTR 

(CINCINNATI) CINCINNATI, OH 

Project Period: 2001/09/30-2006/08/31 

DESCRIPTION (provided by applicant): The condition of "dry eye" results from diminished production 

of the aqueous tear component. Some forms of dry eye are age-related and more common in females. 

Other manifestations of dry eye are associated with inflammatory disorders such as rheumatoid arthritis 

and Sjogren's syndrome. In rare cases there is a congenital absence of the lacrimal gland. Regardless of 

the etiology, in severe cases the absence of lubrication to the cornea can result in ulceration and blindness. 

The frequency of occurrence of dry eye means that it is a significant public health problem. Despite our 

long-standing knowledge of the dry eye condition and its potentially severe consequences, study of 

lacrimal gland development using techniques of modern molecular genetics has only recently been 

initiated. These studies took advantage of a transgene reporter that marked the epithelial component of the 

gland and allowed us to easily follow the process of budding and branching that occurs during 

development of the gland. Ultimately, this work showed that both the transcription factor Pax6 (expressed 

in gland epithelium) and the growth factor FGF10 (expressed in periorbital mesenchyme) were required 

for normal lacrimal gland development. With the current proposal, it is our intention to build on these 

studies and examine the role of the transcription factor Barx2, the bone morphogenetic proteins 4 and 7 

and the adhesion molecule Ng-CAM in gland morphogenesis. The Specific Aims include (1) an 

examination of whether an FGF1O gradient is a controlling factor in gland morphogenesis, (2) a 

determination of how BMPs 4 and 7 can influence lacrimal gland morphogenesis, (3) loss-of-function 

experiments to determine whether the transcription factor Barx2 is required for gland morphogenesis, (4) 

an assessment of whether there is a regulatory relationship between Barx2 and the BMPs, and (5) a 

determination of whether Barx2 regulates the expression of the adhesion molecule LI. Combined, these 

will provide a focussed effort designed to answer questions central to the mechanism of lacrimal gland 

development and may provide an understanding of how to approach treatment of the dry eye condition. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R01EY013143-02S2 

Program Director: FISHER, RICHARD S 

Principal Investigator: LAURIE, GORDON W PHD ANATOMY 

Title: Structure and Function of Ocular Lacritin 

Institution: UNIVERSITY OF VIRGINIA CHARLOTTESVILLE 

 CHARLOTTESVILLE, VA 

Project Period: 2002/08/01-2007/07/31 

Abstract Text Not Available
 

42 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY013143-03 

Program Director: FISHER, RICHARD S 

Principal Investigator: LAURIE, GORDON W PHD ANATOMY 

Title: Structure and Function of Ocular Lacritin 

Institution: UNIVERSITY OF VIRGINIA CHARLOTTESVILLE 

 CHARLOTTESVILLE, VA 

Project Period: 2002/08/01-2007/07/31 

Our entirely rewritten application addresses the lacrimal/corneal axis as a fundamental regulator of ocular 

health. We seek a global understanding of how lacrimal acinar cell secretory control is governed and 

downstream consequences. Modulation of basal and reflex tear secretion is complex, largely unexplored 

and reversible; and plays into the enigmatic etiology of Dry Eye syndromes for which basal and reflex 

tearing capacity is often differentially deficient. Underlying main lacrimal gland 'basal’and 'reflex’tearing 

(terms that describe output at the ocular surface) are the acinar cell 'constitutive', 'constitutive-like', 'minor 

regulated’(basal) as well as 'major regulated’(reflex) secretory pathways - each with particular 

characteristics defined for the most part in other exocrine organs such as the parotid. Hypothetically 

possible is a receptor-mediated autocrine feedback loop(s) in which secretory product(s) released from 

one secretory pathway enhance or diminish secretion from another pathway, a potentially sensitive 

arrangement offering a novel framework for studying lacrimal hyposecretion in Dry Eye. Recently we 

discovered lacritin, an autocrine enhancer of lacrimal acinar cell basal secretion (Sanghi et al, J. Mol. 

Biol. '01; cover issue). Lacritin is highly conserved and released from lacrimal acinar cells by the major 

regulated pathway. It enhances basal tear secretion in a dose dependent manner, and rapidly activates 

both low amplitude calcium signaling and tyrosine phosphorylation. Lacritin also promotes the 

proliferation of downstream ductal cells and calcium signaling by corneal epithelial cells. Estimated cell 

binding affinity is 0.03 - 0.07 nM (versus NGF [0.01 - 1 nM], EGF [0.2 nM], PDGF [0.4 - 0. 7 nM]). 

Expression studies suggest that the lacritin gene is one of the most lacrimal gland-specific described. Our 

working hypothesis is that lacritin release stimulates the minor regulated pathway in a G -protein coupled 

receptor dependent manner, and that ligation of the same receptor in ductal and corneal epithelial cells 

regulates cell turnover. Our specific aims are therefore: (1) to identify and characterize how lacritin 

contacts target cell surfaces, (2) to clarify the identity of the lacritin-dependent secretory pathway, its 

mechanism of activation and significance, and (3) to elucidate lacritin's downstream ductal and ocular 

surface role.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R03EY014013-02 

Program Director: FISHER, RICHARD S 

Principal Investigator: MATHERS, WILLIAM D MD CLIN MEDICAL SCIENCES 

Title: In Vivo Imaging of Leukocyte-Endothelial Dynamics 

Institution: OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND, OR 

Project Period: 2003/04/15-2006/03/31 
 

43 

DESCRIPTION (provided by applicant): The process of leukocyte migration across the vascular 

endothelial barrier is fundamental to the process of inflammation and the response to infection. We will 

quantitate the effect of various medications such as topical corticosteroids, oral nonsteroidal antiinflammatory drugs, and mast cell stabilizers in several of these processes. We have applied intravital 

microscopy in animal systems to visualize, quantitate and analyze this process. Recent advances in 

confocal microscopy have allowed a European group to quantitate leukocyte endothelial rolling and 

sticking in the microvasculature of the human eye. Combining our clinical expertise in confocal 

microscopy and our experience analyzing leukocyte vascular interactions, we propose to utilize in vivo 

confocal technology to quantitate leukocyte rolling and arrest in 4 different human vascular beds: the 

limbus, conjuctiva, episclera, and sclera. With these three specific aims: Aim one, we propose to image 

rolling and sticking of leukocytes in four different normal ocular vascular beds: the conjunctiva, limbus, 

episclera, and sclera. Aim two, we will compare leukocyte-endothelial dynamics in specific vascular beds 

in seven disease states: a) allergic seasonal conjunctivitis, b) Sjogren's syndrome and dry eye, c) 

blepharitis, d) graft versus host disease (GVHD), e) episcleritis, f) scleritis, and g) anterior uveitis. Aim 

three, we will determine the effect of medications including topical prednisolone acetate, a mast cell 

stabilizer (optipranolol), or an oral nonsteroidal anti-inflammatory drug (indomethacin) on endothelialleukocyte dynamics in diseases for which each is frequently prescribed. Our studies will directly clarify 

the pathogenesis of several troublesome and rarely studied ocular disease processes. These studies will 

elucidate the mechanism by which medications alter these processes. Most importantly these studies will 

quantitate a fundamental human biological process in microvascular beds that have not previously been 

imaged. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY003177-24 

Program Director: LIBERMAN, ELLEN S 

Principal Investigator: MCAVOY, JOHNSTON W PHD OTHER AREAS 

Title: LENS DIFFERENTIATION & CATARACT: ROLE OF FGF, RA & WNT 

Institution: UNIVERSITY OF SYDNEY SYDNEY NSW, 

Project Period: 1991/09/30-2007/07/31 

DESCRIPTION (provided by applicant): This project aims to elucidate factors that regulate 

differentiation and growth of the epithelial monolayer. There is growing evidence that members of the 

FGF, RA and Wnt families may play key roles in lens epithelial cell biology. Part one is directed at 

testing the hypothesis that FGF (a low dose), RA and Wnt regulate lens epithelial proliferation, adhesion 

and communication. The effects of these ligands on expression of lens epithelial phenotypic 

characteristics including key molecules, such as cadherins, integrins and connexons, will be investigated 

using RT-PCR, in-situ hybridisation and immunohistochemistry. Part two will test the hypothesis that 

FGF (a low dose), RA and Wnt stimulate signalling cascades which cooperate to stimulate expression of 

key epithelial transcription factors. This will investigate modulation of receptor expression and 

identification of signaling cascades activated by these ligands. Transcription factors studied will be Pax-6, 

Eya-1, Six-3, maf-B, AP2a, RAR/RXR and Foxe-3. Part three will test the hypothesis that TFGbetainduced cataractous changes involve inhibition of FGF, RA and Wnt signalling, and down regulation of 

expression of key epithelial transcription factors. This will investigate how TGFbeta modulates 

expression of FGF, RA and Wnt receptors, signalling molecules and transcription factors (see above). 

Part four will test the hypothesis that reduced Pax-6 expression makes lens epithelial cells more 

susceptible tp TGFbeta-induced cataractous changes. The small eye (Sey) mouse will be investigated to 
 

44 

determine if epithelial cells from this mutant are more sensitive to TGFbeta and, if so, the mechanism(s) 

involved. Understanding the molecular interactions that determine the lens epithelial phenotype is central 

to understanding the molecular basis of cataracts involving aberrant epithelial growth, including PCO. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R01EY005801-19S1 

Program Director: FISHER, RICHARD S 

Principal Investigator: MIRCHEFF, AUSTIN K 

Title: Basal-Lateral/Endomembrane Traffic in Lacrimal Acini 

Institution: UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 1985/04/01-2004/09/29 

Abstract Text Not Available

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 2R01EY005801-20 

Program Director: FISHER, RICHARD S 

Principal Investigator: MIRCHEFF, AUSTIN K 

Title: Basal-Lateral/Endomembrane Traffic in Lacrimal Acini 

Institution: UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 1985/04/01-2009/08/31 

DESCRIPTION (provided by applicant): Sjogren's syndrome (SjS) and other immune-related diseases 

cause lacrimal dysfunction, impaired vision, and ocular surface inflammation in 2 to 4 million Americans. 

Primary lacrimal deficiency (PLD), which also may have an immune-related component, affects at least 6 

million more. These concepts are unified by the hypothesis that: the milieu in the lacrimal glands reflects 

an immunohomeostasis involving regulatory lymphocytes, autoimmune effector lymphocytes, and 

secretory epithelial cells; lymphocyte and inflammatory cell mediators modulate epithelial cell functions; 

and the immunohomeostasis evolves in response to altered epithelial cell functions. However, little is 

known about the triggers that alter epithelial function to initiate the diseases, the reasons they occur more 

frequently in women than in men, and the molecular mechanisms that cause lacrimal dysfunction. The 

investigators have found that chronic stimulation of lacrimal acinar cells with the muscarinic receptor 

(MAChR) agonist, carbachol, causes epithelial secretory quiescence and also activates an aberrant 

endomembrane traffic program that blocks movement to lysosomes, potentially increasing exposure of 

constitutive autoantigens and initiating exposure of previously cryptic epitopes. The G proteins that 

classically couple to MAChR, Gq and G11, are shared by receptors for a wide variety of mediators, and 

their signaling is influenced by the sex hormones. Therefore, the investigators propose that: (a) 

physiological perturbations can initiate inappropriate Gq/G11 signaling that activates the aberrant traffic 

program, and (b) the local environments in SjS and PLD stimulate inappropriate Gq/G11 signaling that 

causes functional quiescence underlying lacrimal dysfunction. Specific Aim 1. What are the signals that 

activate the aberrant membrane traffic program? The central hypothesis is that MAChR remain activated 

and continue to activate Gq/G11. Specific Aim 2. Can chronic stimulation of other receptors also cause 

functional quiescence and activate the aberrant traffic program? The central hypothesis is that these 

changes can be elicited by agonists for receptors that utilize Gq/G11, including histamine, 5-

hydroxytryptamine, PGE2, and estradiol. Specific Aim 3. What traffic effectors are responsible for the 

aberrant program? The central hypothesis is that chronic stimulation decreases dynein motor function but 
 

45 

increases p150(Glued) association with kinesin II, thereby increasing kinesin-mediated traffic. Specific 

Aim 4. How extensively does the aberrant program alter traffic of lysosomal proteins? The investigators 

will use a GFP-cathepsin S fusion protein and confocal microscopy to test the hypothesis that lysosomal 

proteins accumulate in the endosomes. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R03EY013720-03 

Program Director: FISHER, RICHARD S 

Principal Investigator: MIRCHEFF, AUSTIN K 

Title: Prolactin--Autocrine/paracrine factor in lacrimal gland 

Institution: UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 2002/05/01-2005/04/30 

Dry eye is a common problem with a severe impact on the quality of life and potential vision-threatening 

complications. It often results from lacrimal insufficiency caused by immune-related processes, as in 

Sjogren's syndrome, or by hormone changes associated with aging and various physiological states. One 

critical hormonal influence on the lacrimal glands appears to be prolactin. Studies with human subjects, 

hypophysectomized rats, transgenic mice, and acinar cells in primary culture indicate that prolactin can 

impair lacrimal function, even at serum concentrations within the range of normal values. Moreover, the 

source of the prolactin that impairs lacrimal gland function may be the lacrimal glands themselves. The 

lacrimal glands express prolactin mRNA and protein, which may act as an autocrine or intracrine factor 

that in some circumstances may interfere with secretion. This project will use lacrimal acinar cells in 

primary culture to answer the following questions: 1. Does locally expressed prolactin act as an 

autocrine/intracrine factor that supports secretory functions at normal concentrations and impairs them at 

excessive concentrations? Neutralizing antibodies and antisense reagents will be used to minimize 

actions of locally expressed prolactin. Expression constructs will be used to overexpress prolactin. Acinar 

cell morphology, carbachol-induced protein secretion, expression of polymeric immunoglobulin 

receptors, and expression of ion transport proteins will be evaluated for changes related to altered 

prolactin expression. 2. Do altered forms of prolactin (16 kDa and phosphorylated 24 kDa) that have 

inhibitory effects in other cells inhibit lacrimal secretory function? The effects of overexpressed and 

added forms will be tested as in Specific Aim 1. 3. Does lacrimal prolactin act as a paracrine factor 

contributing to autoimmune activation? Antisense reagents and expression constructs will be used to 

suppress or enhance acinar cell prolactin expression, and the modified cells will be tested for their ability 

to promote proliferation of autologous lymphocytes in mixed cell reactions. This work will advance our 

understanding of significant mechanisms in lacrimal physiology, and it will have immediate implications 

for the direction of other studies now in progress. It also has the possibility of stimulating much work 

well beyond its present scope, including epidemiological studies aimed at identifying sub-populations of 

lacrimal deficiency patients with different etiologies, followed by design of appropriate, highly specific 

therapies.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R01EY015109-01 

Program Director: LIBERMAN, ELLEN S 
 

46 

Principal Investigator: MITTAG, THOMAS W PHD BIOCHEMISTRY-UNSPEC 

Title: Retinal ganglion cell loss in aging mice. 

Institution: MOUNT SINAI SCHOOL OF MEDICINE OF NYU NEW YORK, NY 

Project Period: 2004/07/10-2008/05/31 

DESCRIPTION (provided by applicant): The primary aim of this project is to characterize the timecourse and pattern of retinal ganglion cell (RGC) death in the highly inbred DBA 2J mouse and to 

establish this mouse as an in-vivo test system for potential neuroprotective interventions (drugs, genetherapy, etc.). DBA/2 mice spontaneously develop a pigmentary glaucoma with elevated ocular pressure 

(IOP). There is a significant gender-difference in the time of onset and progression of retinal pathology. 

Severe IOP-induced loss of RGC occurs much earlier in life in the female DBA/2 mouse than the male or 

very old normal mice (C57 BL/6J). Experiments involving orchidectomy, supplementation with estrogen, 

testosterone or progesterone and chronic treatment with aromatase inhibitors are aimed to support the 

hypothesis that aromatase-derived estrogen (from testosterone) delays retinal pathology in male DBA/2 

mice. The relationship of RGC loss to the elevated IOP history of individual eyes and to the degenerative 

changes in the superior colliculus of the brain receiving input from that eye will also be investigated. 

Mice chronically treated (3-4 months) with several classes of drugs that are partially effective in shortterm treatments of acute induced rat RGC death models, will be evaluated by mapping of RGC in the 

entire retina. The classes of drugs to be tested include an alpha-adrenergic agonist, a beta-adrenergic 

antagonist, inhibitors of the NOS-2 enzyme, and the anti-Parkinson's agents deprenyl and memantine. The 

drug experiments are aimed at establishing proof-of-principle that agents having neuroprotective 

properties in cultures or acute model systems can be effective in a slow, spontaneous neurodegenerative 

condition, such as RGC death, when administered as chronic systemic therapy. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5K23EY013766-03 

Program Director: REDFORD, MARYANN 

Principal Investigator: NICHOLS, JASON J 

 OD OPTOMETRY 

Title: The Contact Lens and Dry Eye Study 

Institution: OHIO STATE UNIVERSITY COLUMBUS, OH 

Project Period: 2002/02/01-2007/01/31 

The primary goal of this K23 proposal is to train the Jason J. Nichols, OD MS is an independent clinicianscientist. To achieve this goal, a five-year training program is proposed which emphasizes mentoring and 

formal coursework in 1) vision science leading to a PhD from The Ohio State University College of 

Optometry and in 2) biostatistics and epidemiology leading to an MPH degree from The Ohio State 

University College of Medicine and Public Health. In 1995, the National Eye Institute (NEI) sponsored 

dry eye workshop report identified contact lens-related dry eye as a major sub-classification of dry eye 

syndrome. Yet, there has been little clinical research sponsored by the NEI to study the etiology or 

epidemiology of contact lens-related dry eyes since that time. The proposed training will provide Dr. 

Nichols with the necessary patient-oriented research skills to conduct an epidemiologic study of contact 

lens-related dry eye, which has been carefully designed to complement and enhance those skills obtained 

during the development period. Contact lens-related dry eye may severely impact ocular health by leading 
 

47 

to desiccation of the corneal epithelium or an increased incidence of infectious disease. The relation 

between contact lens dehydration and evaporative changes in the tear film needs to be understood as they 

may be the primary cause of contact lens-related dry eye. A cross-sectional/nested case-control study will 

be conducted and the analyses will address risk factors thought to be associated with contact lens-related 

dry eye. In the cross-sectional phase of the study (Phase I), we will characterize and elucidate the 

functional significance of the discrepancy between the frequency and severity of dry eye symptoms 

during contact lens wear. In the nested case-control phase of the study (Phase II), we will test the 

hypothesis that evaporative factors including contact lens characteristics, tear film changes, Meibomian 

gland disease, and blanking patterns are associated with an increased risk for contact lens-related dry eye. 

The long-term objective of this research is to contribute to a better understanding of the etiology and risk 

factors for contact lens-related dry eye so that progress can be made toward its prevention. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5U10EY012118-05 

Program Director: DUDLEY, PETER A 

Principal Investigator: PERICAK-VANCE, MARGARET A PHD :HUMAN GENETICS 

Title: UNIFYING GENETICS EPIDEMIOLOGY OF MACULAR 

 DEGENERATION 

Institution: DUKE UNIVERSITY DURHAM, NC 

Project Period: 2000/06/15-2005/05/31 

Age-related macular degeneration (AMD) is the most common cause of severe vision loss among 

individuals over age 50 in the U.S. The socioeconomic impact is considerable, and is expected to become 

greater as the U.S. population ages. Unfortunately, treatment options remain limited because the etiology 

of this devastating disease remains unknown. Considerable evidence implicates a combination of genetic, 

environmental, and biological factors in the pathogenesis of AMD as such suggested genetic effect 

involves the ATP-binding transporter (ABCR) gene. We thus hypothesize that underlying susceptibility 

gene(s) are critical to the development of AMD, and likely interact with environmental factors to trigger 

both the development and progression of the disease. The purpose of this study is to elucidate the genetic 

susceptibility to the development of AMD and to analyze the interaction of these genes with 

environmental influences. We will use both candidate gene and genomic screening approaches to identify 

these genes. Already identified genetic and environmental risk factors will be evaluated and current 

statistical methodologies will be adapted to examine the possible interactions. Multiplex (greater than 1 

AMD affected/family) families will be recruited for the genetic analyses and detailed risk factor 

information will be collected on all study participants. Family-based association methods will be used to 

evaluate candidate genes, environmental risk factors and gene- gene and gene-environment interactions. 

The information derived from this study will further our understanding of this complex disease. The 

identification of specific susceptibility genes and evaluation of gene-environment interaction will be 

crucial for future studies in unraveling the etiology of AMD and developing better treatments. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY011915-07 

Program Director: FISHER, RICHARD S 

Principal Investigator: PFLUGFELDER, STEPHEN MD 
 

48 

Title: Pathogenesis of Conjunctival Squamous 

Institution: BAYLOR COLLEGE OF MEDICINE HOUSTON, TX 

Project Period: 1997/08/01-2006/03/31 

DESCRIPTION (provided by applicant): Our research has identified that changes in the ocular surface 

environment of dry eye, such as a hyperosmolar tear film, stimulate the production of pro-inflammatory 

cytokines by the ocular surface epithelia. Our preliminary data suggests that these cytokines, particularly 

interleukin-1 (IL-1) and TNF-alpha, may play a key role in the pathogenesis of the epithelial and 

immuno-pathology of keratoconjunctivitis sicca, (KCS) the ocular surface disease of dry eye. Four 

proposed Specific Aims will test this theory. Aim I will confirm whether experimentally induced dry eye 

in mice stimulates the production and release of pro-inflammatory cytokines by the ocular surface 

epithelium that promote ocular surface inflammation and KCS. Aim 2 will determine whether 

hyperosmolar stress stimulates the production of pro-inflammatory cytokines by the ocular surface 

epithelium by activating the p38 stress activated protein kinase pathway. Aim 3 will study the expression 

of IL-1 and TNF-alpha receptors on the ocular surface and determine if there are differences in the 

expression of these receptors and their soluble antagonists between normal and dry eyes. Aim 4 will 

investigate the effects of the pro-inflammatory cytokines of dry eye on the expression of matrix 

metalloproteinase enzymes (MMPs) and mucins on the ocular surface. These factors that have been 

implicated in the disruption of ocular surface barrier function and homeostasis in KCS. These studies will 

provide clinically relevant information regarding the role of inflammation and its cytokine mediators on 

the pathogenesis of the ocular surface disease of dry eye, a condition experienced by over 10 percent of 

the population over the age of 30. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY010550-09 

Program Director: FISHER, RICHARD S 

Principal Investigator: SCHECHTER, JOEL E 

Title: Prolactin as a Lacrimal Gland Immunoregulator 

Institution: UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 1994/04/01-2006/12/31 

Abstract Text Not Available

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R01EY010550-09S1 

Program Director: FISHER, RICHARD S 

Principal Investigator: SCHECHTER, JOEL E 

Title: Prolactin as a Lacrimal Gland Immunoregulator 

Institution: UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA 

Project Period: 1994/04/01-2006/12/31 

Abstract Text Not Available
 

49 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R41EY015376-01 

Program Director: HELMSEN, RALPH J 

Principal Investigator: SHEPPARD, JOHN D MD 

Title: Stimulation of Tear Secretion by a Novel Glycoprotein 

Institution: EYERX RESEARCH, INC. NORFOLK, VA 

Project Period: 2004/09/30-2005/09/29 

DESCRIPTION (provided by applicant): Dry eye is a ubiquitous, often overlooked, underdiagnosed and 

poorly understood affliction of the ocular surface. This common opthalmological complaint can markedly 

affect a patient's quality of life. As a multifactorial disease, dry eye has hyposecretory, auto-immune, 

inflammatory, hormonal, neurogenic, toxic, and iatrogenic components. Common to all etiologies is a 

decrease in both volume and quality of tear secretion. Current therapy ranges from topical application of 

aqueous, oil and gel tear film constituent replacement "artificial" tears, to topical anti-inflammatory drugs, 

to oral secretagogues. There are currently no approved topical agents indicated for enhancement of tear 

flow and production, which would address the primary defect in aqueous deficiency dry eye disease. 

Lacritin is a stable, novel human tear glycoprotein produced solely by lacrimal and salivary glands. It 

binds to and stimulates a rapid, sustained release of calcium in cultured corneal epithelial cells, which 

suggests topical application of lacritin may stimulate the cornea/lacrimal gland axis to increase tear 

production. Based upon these properties elucidated in cell culture, we hypothesize that lacritin has 

potential as a therapeutic agent to promote tear production. Compared to current therapy, as an ocularspecific prosecretory glycoprotein, lacritin has a unique mechanism of action. We expect that topical 

application of lacritin will increase tear production by stimulation of the lacrimal gland/corneal axis. The 

long-term goals of this translational research project are to develop lacritin as an efficacious, nontoxic 

topical treatment. Specific aims for this proposal are (1) demonstration, using an in vivo rabbit model, of 

the ability of lacritin to increase tear production after topical administration, (2) determination of the 

effect of lacritin on the normal composition of tears, and (3) examination of lacritin-treated ocular tissues 

for signs of adverse effects. The primary outcome measurement is lacritin's ability to increase tear 

production. In vivo analysis also includes confocal microscopy, slit lamp biomicroscopy, digital 

photography, application of the MacDonald-Shadduck Scale for Ocular Toxicity, tear break up time, vital 

dye assessment with fluorescein and Lissamine green, and Schirmer's test for tear production.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R21EY015671-02 

Program Director: SHEN, GRACE L 

Principal Investigator: SOSNE, GABRIEL MD 

Title: Thymosin beta 4 and Autoimmune Ocular Surface Disease 

Institution: WAYNE STATE UNIVERSITY DETROIT, MI 

Project Period: 2003/09/30-2005/08/31 

DESCRIPTION (provided by applicant): Keratoconjunctitivitis sicca (KCS), or dry eye disease, is one of 

the most common conditions seen by ophthalmologists and affects 15% of those from 65-84 years of age, 

or 4.3 million Americans. The pathophysiology of dry eye includes immune-mediated inflammation 

involving both the ocular surface and the lacrimal gland. While knowledge of the pathology of dry eye 
 

50 

disease has improved significantly during recent years, the mainstay of treatment, ocular lubrication, 

provides only palliative relief at best to patients with severe dry eye disease. Therefore, attention has 

turned to immunomodulation as a therapeutic approach for I severe dry eye disease, especially for that 

seen in autoimmune diseases like Sjogren's syndrome, I rheumatoid arthritis, and systemic lupus 

erythematosus (SLE). Available agents such as corticosteroids have I considerable side effects that render 

them therapeutically impotent in a number of patients. Recently, the FDA approved Cyclosporine A 

(CSA), 0.5% (Restasis) for the treatment of moderate to severe dry eye. However, 85% of CSA-treated 

patients did not experience a significant increase in tear production. Therefore, a therapeutic agent that 

could reliably decrease immune-mediated ocular surface damage without significant adverse effects in a 

large proportion of affected patients would constitute a major therapeutic advance, particularly for dry eye 

disease. Thymosin beta 4 (Tb4) promotes corneal wound healing and reduces inflammation in mice after 

chemical injury to the eye. Since Tb4 has both anti-inflammatory and wound healing properties, it is an 

ideal candidate for evaluation in an autoimmune model of dry eye. Two specific aims are proposed to test 

the overall hypothesis of this application that Tb4 modulates lacrimal gland, corneal and conjunctival 

inflammation in an animal model of autoimmune dry eye disease. 1) To test the hypothesis that Tb4 alters 

production of cytokines, chemokines and specific matrix metalloproteinases (MMPs) in a murine model 

of Sjogren's syndrome; 2) To test the hypothesis that Tb4 alters autoimmune ocular surface damage in the 

MRL/Ipr mouse by decreasing lacrimal gland inflammation and conjunctival squamous metaplasia. By 

identifying Tb4 as a novel wound healing and anti-inflammatory agent to protect the ocular surface from 

inflammatory and immune tissue injury, it is aimed to substantiate the potential clinical usage of Tb4 for 

the majority of patients who are not relieved by currently available therapies.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R03EY015115-01 

Program Director: LIBERMAN, ELLEN S 

Principal Investigator: STAMER, W DANIEL PHD PHARMACOLOGY 

Title: SELENIUM-INDUCED GLAUCOMA 

Institution: UNIVERSITY OF ARIZONA TUCSON, AZ 

Project Period: 2003/12/01-2006/11/30 

DESCRIPTION (provided by applicant): Glaucoma, the second leading cause of irreversible blindness in 

the United States, is a group of disorders characterized by a progressive loss of retinal ganglion cells with 

associated loss of vision that is in most cases coincident with elevated intraocular pressure (IOP). Today 

and in the foreseeable future, those with glaucoma are clinically managed with pharmaceutical agents that 

lower IOP. Elevated IOP in those with glaucoma results from defective regulatory processes in the 

outflow pathway. Consequently, a current area of focus for glaucoma research and a program priority area 

for the National Eye Institute (Glaucoma Panel Program Objective #3) is to understand the molecular and 

cellular mechanisms that underlie the regulation of fluid flow through the human outflow pathway. 

During a recent safety review in a current selenium-supplementation intervention trial (the Nutritional 

Prevention of Cancer Trial) an increased incidence of primary open-angle glaucoma amongst participants, 

particularly women, in the selenium treatment group was uncovered. In the present proposal, we examine 

the effects of selenium on the biology of human trabecular meshwork cells and outflow function both in 

the presence and absence of 17 beta-estradiol. Hypothesized effects of selenium on outflow function are 

consistent with demonstrated effects of selenium on other cell types that include alterations in 

extracellular matrix turnover, cell cycle arrest and induction of apoptosis. The present study will examine 

these endpoints in cell and organ culture models and thus is innovative for at least two reasons: First, 
 

51 

determination of selenium effects on cell biology in human outflow pathway will provide insight into 

and/or support for critical regulatory mechanisms that control outflow facility. Second, selenium 

treatment of outflow tissues may provide a novel glaucoma model to study changes in the outflow 

pathways at the molecular and cellular level in a controlled manner. If successful, results obtained from 

these investigations will provide a basic understanding of selenium effects on aqueous outflow facility, 

uncover novel therapeutic targets for glaucoma treatment and generate a foundation for future 

investigations.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY005612-18 

Program Director: FISHER, RICHARD S 

Principal Investigator: SULLIVAN, DAVID A PHD 

Title: Gender, sex steroids and dry eye syndromes 

Institution: SCHEPENS EYE RESEARCH INSTITUTE BOSTON, MA 

Project Period: 1985/09/30-2005/11/30 

DESCRIPTION (provided by applicant): The preocular tear film plays a critical role in maintaining 

ocular surface integrity, protecting against microbial challenge and preserving visual acuity. Tear film 

dysfunction, in turn, may severely impact the eye and lead to desiccation of the corneal epithelium, 

ulceration and perforation of the cornea, an increased incidence of infectious disease, and pronounced 

visual impairment and blindness. Countless people suffer from tear film disorders, which are termed dry 

eye syndromes and are classified into 2 major types: aqueous-deficient and evaporative. Aqueousdeficient dry eye is due to decreased tear secretion from the lacrimal gland. An example is Sjogren's 

syndrome, a common autoimmune disease that afflicts primarily women and destroys the lacrimal gland. 

Evaporative dry eye is typically caused by meibomian gland dysfunction and may be a major cause of dry 

eye during menopause, use of estrogen hormone replacement therapy (HRT) and aging. The long range 

objectives of this grant application are to test our hypotheses that: (1) sex steroids are extremely important 

in the physiological regulation of the lacrimal and meibomian glands, as well as the production of the tear 

film; and (2) gender, sex steroid hormones, and in particular androgen deficiency, are critical etiologic 

factors in the pathogenesis of both aqueous-deficient and evaporative dry eye syndromes. Experimental 

procedures include mouse models, DNA hybridization arrays (i.e. gene chips), RT-PCR, ribonuclease 

protection assays, Northern, slot and Southern blots, in situ hybridization, cell cultures, immunoassays, 

HPLC/mass spectrometry, enzyme assays, histology, image analysis, hormone reconstitution 

experiments, as well as clinical studies with humans. Our specific aims are to: (1) identify the genes and 

proteins that mediate the gender-related differences in, and the sex steroid control of, lacrimal glands in 

normal and autoimmune (i.e. Sjogren's syndrome) mice; (2) identify the genes and proteins involved in 

the gender-associated variations in, and the sex steroid regulation of, the mouse meibomian gland; and (3) 

determine the specific effects of HRT use (estrogen, or estrogen plus progesterone), with or without 

androgen supplementation, on the ocular surface of postmenopausal women. Results from the studies 

should significantly advance our understanding of the processes by which gender and sex steroids 

influence the anterior segment of the eye. In addition, findings may have health relatedness for the eye, 

because they: (1) explore the regulation of the tear film; and (2) may lead to the development of specific 

therapies for the clinical treatment of dry eye syndromes. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 2R01EY012689-04A2 
 

52 

Program Director: SHEN, GRACE L 

Principal Investigator: TROUSDALE, MELVIN D 

Title: Anti-Inflammatory Genes in Autoimmune Dacryoadenitis 

Institution: DOHENY EYE INSTITUTE LOS ANGELES, CA 

Project Period: 2000/05/01-2009/06/30 

DESCRIPTION (provided by applicant): Dry eye affects approximately 10 million Americans, most of 

whom are women. An estimated 2 million cases of Sjogren's syndrome exist in America. Our long-term 

goal is to elucidate the mechanism of immunopathogenesis of autoimmune dacryoadenitis and to 

determine the impact of vlL-10 and TNF-inhibitor gene expression on the disease. In an in vivo rabbit 

model of autoimmune dacryoadenitis, lymphocytes proliferate in a mixed cell reaction with purified 

autologous lacrimal gland epithelial cells and, when injected back into the rabbit's own contralateral 

gland, induce intense focal lymphocytic infiltration, thus creating a model for autoimmune 

dacryoadenitis. Tear production is reduced and tear stability is decreased in the dysfunctional lacrimal 

gland while rose bengal staining of the corneal surface is increased. CD4+ T cells and CD18+ cells 

increase significantly in the immune infiltrates in the gland, and the CD4+ to CD8+ T cell ratio increases 

as it does in Sjogren's syndrome. Aim 1. Characterize the cells that proliferate in autologous mixed cell 

reactions. Hypothesis 1a. Autoreactive CD4+ T cells proliferate in the mixed cell reaction and secrete 

proinflammatory cytokines (e.g. IL-2, TNF b, and IFNy,). Hypothesis 1b. Lacrimal autoimmunity is a 

normal phenomenon and active functioning regulatory T cells ordinarily prevent normal autoimmunity 

from developing into clinical disease. Aim 2. Identify the autoreactive T cell responsible for inducing 

autoimmune dacryoadenitis and monitor the progression of the disease. Hypothesis 2a. Purified 

lymphocyte population that proliferate in mixed cell reactions induce autoimmune dacryoadenitis. 

Hypothesis 2b. Autoimmune dacryoadenitis can be induced by the animal's own activated lymphocytes 

administered at sites other than the lacrimal gland (e.g. intravenous or subcutaneous), and this will result 

in systemic disease involving the salivary glands and kidneys. Aim 3. Develop gene transfer therapeutic 

strategies using an AAV vector (AAV-tetON-vlL- 10) with an inducible promoter for treating 

autoimmune dacryoadenitis and explain the mechanism of action of vlL-10 on effector T cells. 

Hypothesis 3a. Long-term expression of vlL-10 gene in the lacrimal gland suppresses effector T cell (e.g. 

CD4+ cells) proliferation, but not suppressor T cell activity. Hypothesis 3b. vlL-10 suppresses CD4+ T 

cell proliferation by down regulating expression of Th 1 cytokines IL-2, TNF-b and interferon-y. Aim 4. 

Elucidate the exit pathway of transgene product from the transduced acinar cell. Hypothesis 4a. 

Intracellular trafficking of vlL-10 results in the anti-inflammatory cytokine exiting the transduced 

lacrimal cells via both apical and basolateral membranes. The overall study will determine the effector 

cell phenotype, their secreted proinflammatory cytokines and the impact of over expression of vlL-10 on 

Th 1, Th2 and Th3 responses during progression and regression of the autoimune disease. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R01EY010056-10S1 

Program Director: FISHER, RICHARD S 

Principal Investigator: WILSON, STEVEN E MD 

Title: CORNEAL EPITHELIAL CELL GROWTH FACTORS AND RECEPTORS 

Institution: CLEVELAND CLINIC LERNER COL/MED-CWRU Nashville,, TN 

Project Period: 1994/08/01-2005/06/30 
 

53 

Abstract Text Not Available

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R21EY015457-01 

Program Director: FISHER, RICHARD S 

Principal Investigator: YIU, SAMUEL C PHD 

Title: Bioartificial Lacrimal Gland 

Institution: DOHENY EYE INSTITUTE LOS ANGELES, CA 

Project Period: 2004/05/01-2006/04/30 

DESCRIPTION (provided by applicant) Millions of Americans have dry eye disease. Individuals plagued 

by the discomfort, burning, irritation, photophobia, and other symptoms of dry eye disease also have 

blurred vision, contact lens intolerance, the inability to produce emotional tears, and an increased risk of 

ocular surface damage and infection. In the United States alone an estimated 2 million Sjogren's 

Syndrome patients have dysfunctional lacrimal glands and severe dry eye and there is no satisfactory 

treatment. A bioartificial lacrimal gland would greatly benefit these patients. The new field of tissue 

engineering has built on the interface between materials science and biocompatibility to create the 

possibility of developing a bioartificial lacrimal gland. Our three specific aims are: 1) To identify the 

optimal biomaterials for use as the substrate for the growth of rabbit lacrimal epithelial cells in a threedimensional scaffold. 2) To test the physiological properties of these bioengineered tissues, including 

secretory functions and electrophysiological activities. 3) To establish strategies and data for the design 

and development of a bioartifical lacrimal gland as the basis for a BRG grant proposal using the RO1 

funding mechanism. This work will advance our understanding of how lacrimal epithelial cells function 

in this artificial environment and lead to the development of an RO1 proposal. Ultimately, we envision a 

bioengineered lacrimal gland system, to be surgically implanted in periocular tissues that will produce 

sufficient tear flow to maintain the health of the ocular surface. Such a device could relieve the symptoms 

of millions of dry eye patients; and it could possibly make obsolete the frequent daily use of lubricant eye 

drops, saving patients the time and effort of medication use and saving millions of dollars annually in the 

purchase of lubricating eye drops. 

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 1R03EY015134-01 

Program Director: FISHER, RICHARD S 

Principal Investigator: YOUNG, WILLIAM W PHD 

Title: OCULAR SURFACE MUCIN ppGaNTase GLYCOSYLTRANFERASES 

Institution: UNIVERSITY OF LOUISVILLE LOUISVILLE, KY 

Project Period: 2004/05/01-2007/04/30 

DESCRIPTION (provided by applicant): The mucus layer, secreted primarily by the conjunctival goblet 

cells but also by the corneal and conjunctival epithelia, is a critical protective layer for the ocular surface; 

shielding it from pathogenic and environmental challenges. Mucins are a heterogeneous group of highly 

glycosylated proteins that are present both on the ocular surface cells and as major soluble components of 

tear fluid. The first and rate-limiting step of O-glycosylation of mucins requires the action of at least one 
 

54 

isoform of the UDPGalNAc: polypeptide N-Acetylgalactosaminyltransferase (ppGaNTase) family of 

glycosyltransferases. Without glycosylation, mucins would lack the viscoelastic properties required for 

proper function. The hypothesis of this project is that one cause of dry eye disease is abnormal mucin 

glycosylation due to altered expression of ppGaNTase isoforms. In the first aim we will compare the 

levels of mRNA expression of ppGaNTase isoforms in normal and dry eye patients by real-time PCR 

using the Taqman technique. The results will provide the first complete analysis of the expression of this 

critical glycosyltransferase family in human ocular tissues and point to one possible cause of human dry 

eye disease. In the second aim we will determine which ppGaNTase isoforms are responsible for 

glycosylation of specific mucin types using RNA interference and inhibitors of ppGaNTase action. First, 

we will determine which ppGaNTase isoforms are expressed at the mRNA level in human corneal and 

conjuncrival cell lines by real-time PCR. Second, we will use gene silencing by small interfering RNAs 

(siRNA) to specifically silence each ppGaNTase isoform and then determine by Western blotting whether 

silencing of one ppGaNTase isoform results in altered glycosylation of each mucin type. As a positive 

control for ablation of mucin glycosylation, we will treat cells with inhibitors of the ppGaNTase family. 

The results of RNA interference will enable us to obtain the first evidence in whole ocular cells as to 

which ppGaNTase isoforms are required for the glycosylation of particular mucin types.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 5R01EY012383-06 

Program Director: SHEN, GRACE L 

Principal Investigator: ZOUKHRI, DRISS PHD MEDICINE AND IMMUNOLOGY 

Title: Stimulus-Secretion Coupling in Diseased Lacrimal Gland 

Institution: TUFTS UNIVERSITY BOSTON BOSTON, MA 

Project Period: 1999/01/01-2007/07/31 

DESCRIPTION (provided by applicant): Sjogren's syndrome, a systemic inflammatory autoimmune 

disease which occurs almost exclusively in females, is the leading cause of aqueous tear deficient dry eye. 

To date there is no cure for this disease and the precise mechanisms responsible for the decreased tear 

secretion are largely unknown. Studies from this laboratory point to a potentially pivotal role of the 

proinflammatory cytokines, interleukin-1alpha (IL-1a), IL-1beta (IL-lb), and tumor necrosis alpha 

(TNFa), in the impaired function of the lacrimal gland associated with Sjogren's syndrome. Specifically, 

we found that these cytokines have a dual target in the lacrimal gland: the nerve endings (i.e., inhibition 

of neurotransmitter release) and the epithelial cells (i.e., inhibition of lacrimal gland protein secretion). 

However, the mechanism(s) by which these cytokines interfere with lacrimal gland nerve endings and 

lacrimal gland acinar epithelial cell functions remain to be elucidated. Thus, the long term objective of the 

present proposal is to define the intracellular signaling pathways activated by proinflammatory stimuli to 

inhibit lacrimal gland secretion. A second objective is to test the effects of selective inhibitors of these 

pathways on lacrimal gland secretion using a murine model of Sjogren's syndrome. To obtain these goals, 

the following specific aims have been proposed: (1) define the signaling pathways activated by 

inflammatory stimuli to inhibit neurotransmitter release and lacrimal gland secretion; (2) determine if 

JNK, ERK, and iNOS are involved in the impaired lacrimal gland secretion associated with Sjogren's 

syndrome; and (3) determine if ICE activity is necessary for inflammation-induced inhibition of 

neurotransmitter release and lacrimal gland secretion. Lacrimal gland slices will be prepared from 

diseased and control female mice. Activation of JNK, ERK, and iNOS will be measured by western 

blotting. The release of neurotransmitter from lacrimal gland nerve endings and protein secretion will be 
 

55 

measured spetrophotometrically. Selective inhibitors of JNK, ERK, and/or iNOS will be given 

subcutaneously to diseased and control female mice.

Date Run: 03/16/05 PUBLIC ABSTRACTS 

Grant: 3R01EY012383-06S1 

Program Director: SHEN, GRACE L 

Principal Investigator: ZOUKHRI, DRISS PHD MEDICINE AND IMMUNOLOGY 

Title: Stimulus-Secretion Coupling in Diseased Lacrimal Gland 

Institution: TUFTS UNIVERSITY BOSTON BOSTON, MA 

Project Period: 1999/01/01-2005/07/31 

Abstract Text Not Available

Project Number: 1 Z01 EY000312-08 

LBC: LMOD 

Title: Estradiol Prevents Cataracts in Female But Not Male Lenses 

HN or SAC code: HNW299 

PI(s): Deborah A. Carper, PhD (MT , NEI ) 

Keywords: cataract, transforming growth factor-beta, alpha smooth muscle actin, estrogen 

SUMMARY: Age-related cataracts occur more frequently in women than in men of comparable 

age. It is believed that this is due to the loss of estrogen after menopause. Support for this 

hypothesis comes from epidemiological studies, which show that hormone replacement therapy 

reduces the risk of cataract, and from animal studies, which show that estradiol prevents TGFbeta-induced anterior subcapsular cataracts in ovariectomized rats. We extended the latter 

observation by testing whether estradiol protects against TGF-beta-induced cataracts in lenses 

from normal male and female rats. Our results showed that in the presence of low concentrations 

of TGF-beta2 (0.15 ng/ml), cultured male rat lenses developed twice as many cataract plaques as 

female rat lenses. Estradiol (10-8M) prevented cataracts in female lenses, but not male lenses. In 

parallel, the anterior subcapsular cataract marker, alpha-smooth muscle actin, was up regulated 

in both male and female rat lenses, but down regulated only in female lenses in the presence of 

estradiol. These findings suggest that there may be sex-specific differences in the levels of 

estrogen receptors. TGF-beta2-induced cataracts serve as a model of human anterior subcapsular 

cataracts and secondary cataracts, with many phenotypic and biochemical similarities. The 

results of our study suggest that estradiol could be a therapeutic option, although, the sex-related 

response must first be tested in human lenses. 

Project Number: 1 Z01 EY000367-05 

LBC: DIR 

Title: Ocular Surface Disease 

HN or SAC code: HNW4 
 

56 

Lead Investigator(s): Janine A. Smith, MD (DECR , NEI ) 

Supervisor of Record: Sheldon S Miller , Ph.D. (DIR , NEI ) 

Keywords: Dry eye, keratoconjunctivitis sicca,Sjogren's Syndrome, Premature Ovarian Failure, 

Cyclosporine A, cornea 

SUMMARY: This program is focused upon ocular surface immune-mediated diseases. We 

recently completed a masked trial of Cyclosporine eye drops for the treatment of 

keratoconjunctivitis sicca. We found elevated and comparable conjunctival inflammatory cell 

sub-populations and markers of immune activation (MHC Class II and adhesion molecules) in 

patients with both Sjogrens' Syndrome, a systemic autoimmune disease, aas well as, in the 

common form of dry eye. Our research has provided tangible evidence of an inflammatory basis 

for dry eye and confirms the rationale of anti-inflammatory therapy for its treatment, which 

represents a significant change in treatment strategy for this disease. We have also reported 

several of our findings on the immunopathogenesis of conjunctival manifestations of 

keratoconjunctivitis sicca. In addition, we have published a novel manifestation of Wegener's 

granulomatosis, tarsal-conjunctival disease which is characterized by signficant conjunctival 

cicatrization, scarring and increased risk of visual loss. We have also been investigating the 

treatment of the autoimmune exocrinopathy, Sjogren's Syndrome, which is associated with a 

particularly severe form of dry eye, in collaboration with the NIDCR, in 3 masked, placebocontrolled trials of DHEA, Thalidomide and Etanercept treatment. All 3 trials have been 

completed and the papers submitted for publication. In addition, we have also continued to work 

on validation of outcome measures for ocular surface disease and have published our findings 

which willfacilitate the use of ocular surface vital dye staining as an outcome measure for 

clinical trials. This work is ongoing. In addtion, we have also identified women with Premature 

Ovarian Failure as a new population of patients at risk for the development of ocular surface 

disease. Compared to age-matched women, significantly more patients with Premature Ovarian 

Failure use ocular lubricants and have objective signs and symptoms of dry eye. These patients 

scored significantly worse than controls on all 3 symptom questionnaires used and showed 

significantly more eye damage measured by ocular surface vital dye staining using validated 

grading schemes. These findings suggest that the dysregulation of hormones and immunologic 

dysfunction seen in Premature Ovarian Failure may play a role in the pathogenesis of ocular 

surface disease in these patients. This paper has been accepted for publication by Archives of 

Ophthalmology. 
 

57 

National Heart, 

Lung, and Blood 

Institute 

 (NHLBI) 
 

58 

National Heart, Lung, and Blood Institute 

Menopause-Related Research 

Because many of the diseases and conditions that fall within the NHLBI mandate (e.g., coronary 

disease, hypertension, congestive heart failure, chronic obstructive pulmonary disease) primarily 

affect older people, many postmenopausal women are being studied in the Institute=s clinical 

research programs. This document focuses specifically on NHLBI-supported research in women 

that is related to reproductive hormonal status or to changes in health risks that occur as women 

pass through menopause. 

Women=s Health Initiative

The Women=s Health Initiative (WHI) is a complex multicenter project examining strategies for 

the prevention and control of the most common causes of death, disability, and impaired quality 

of life among postmenopausal women, including cardiovascular disease, breast and colorectal 

cancers, and osteoporotic fractures. Initiated in 1991 with planned completion in 2007, the WHI 

is conducted as a consortium effort led by the NHLBI in cooperation with the Office of Research 

on Women=s Health, the National Cancer Institute, and the National Institute of Arthritis and 

Musculoskeletal Diseases. Recruitment was completed in 1998. Over 68,000 women of diverse 

racial, ethnic, geographic, and socioeconomic background are participating in three overlapping 

randomized controlled Clinical Trials (CT), and an additional 93,676 women are enrolled in a 

parallel Observational Study (OS). A third component, the Community Prevention Study, 

focused on community-based prevention strategies to enhance adoption of healthful behaviors 

and was conducted by the Centers for Disease Control and Prevention. 

Clinical Trials 

The CT component is designed to evaluate the effect of: 

1) Low-fat eating pattern in preventing breast and colorectal cancers. 

2) Postmenopausal hormone therapy in preventing coronary heart disease and other 

cardiovascular diseases, with breast cancer as a possible adverse outcome. The estrogenplus-progestin component of the hormone trial was stopped on July 9, 2002, because 

WHI researchers found that the risks of long-term estrogen-plus-progestin therapy 

outweigh its protective benefits. NIH stopped the estrogen-only component on February 

29, 2004 because of increased risk for stroke and no benefit for coronary heart disease. 

(See publications for related papers.) 

3) Calcium and vitamin D supplementation in preventing osteoporotic fractures and 

colorectal cancer. 
 

59 

Observational Study 

The OS is identifying predictors of disease by: 1) examining the associations of known or 

putative risk factors (including biomarkers) to disease status at baseline and during follow-up; 2) 

seeking to find new risk factors using the stored biological samples and data as a resource; and 3) 

examining the effects of change in known or putative risk factors on disease outcome. 

A detailed description of the WHI is available in Controlled Clinical Trials 1998;19:61 B 109. 

A list of publications from the WHI can be found at 

http://www.nhlbi.nih.gov/whi/references.htm. 

Representative NHLBI Research Projects in FY 2004

Project No. Title Investigator Institution

R01 HL028266 Epidemiology of Cardiovascular Risk Kuller U. Pittsburgh 

Factors in Women 

A long-term investigation of the evolution of cardiovascular risk factors and subclinical 

cardiovascular disease from premenopause through menopause.

R01 HL032050 Caffeine Influences on Exercise and Lovallo U. Oklahoma 

Psychological Stress 

An evaluation of the effects of caffeine intake on blood pressure and cortisol secretion, under 

conditions of mental and exercise stress, with an emphasis on variations in response as women 

enter menopause.

R01 HL033177 Positron Tomography in Ischemic Schelbert UCLA 

Heart Disease 

A study of coronary vasomotor function that, in postmenopausal women, will explore protective 

effects of estrogens against coronary atherosclerosis and examine whether these effects are 

negated or modified by progestins, as well as whether adequate protection requires addition of 

statins and antioxidants.

R01 HL034594 Risk Factors for Cardiovascular Manson Brigham & Women=s 

Disease in Women Hospital 

Continued follow-up of the Nurses Health Study cohort, first recruited in 1976, to evaluate 

hypotheses regarding dietary and hormonal risk factors for coronary heart disease and ischemic 

and hemorrhagic stroke.

P01 HL045666 Cardiovascular Benefits of Soy Kaplan Wake Forest U. 

Phytoestrogens 

A group of studies focused on the potential cardiovascular benefits of soy photoestrogen 

supplementation/treatment 
 

60 

P50 HL063494 SCOR in Ischemic Heart Disease: Mendelson New Engl. Med. Ctr. 

Cardiac Estrogen Receptors & MI 

An investigation of the hypothesis that the genetics, expression, and function of cardiovascular 

estrogen receptors and estrogen-regulated target genes mediate protection against ischemic 

diseases and their sequelae, including vascular dysfunction, post-myocardial infarction 

remodeling, and arrhythmias. 

R01 HL067128 Longitudinal Study of the Powell Rush PresbyterianMenopause and Fat Patterning St. Luke=s Med. Ctr. 

A study of the natural history of the accumulation of intra-abdominal fat as women progress 

through menopause. 

R01 HL068639 Hormone Replacement Therapy Psaty U. Washington 

and Prothrombotic Variants 

An assessment of the interaction between hormone therapy and other procoagulant variants as it 

affects the risk of cardiovascular events. 

F32 HL069648 Estrogen and Sympathetically Fadel U. Texas Southwest 

Mediated Vasoconstriction Medical Center 

An examination of the influence of estrogen on the regulation of sympathetic vasocontstriction in 

contracting skeletal muscle to determine the mechanisms by which estrogen may confer vascular 

protection.

R01 HL073108 Reproductive Hormones and Bairey Merz Cedars-Sinai 

Pre-Clinical CVD in Women Medical Center 

A study of the role of reproductive hormones in the progression of pre-clinical cardiovascular 

disease in pre-, peri-, and post-menopausal women. 

R01 HL073410 Clotting Genetic Variant, Hormones, Smith U. Washington 

and Venous Thrombosis 

A study to identify genetic variants in 12 key clotting proteins that may modify the risk of venous 

thromboembolism either independently, through gene-gene interactions, or in the presence of 

hormone use. 

R01 HL074729 Postmenopause CHD Risk: Platelet Bray Baylor College of 

Genes and Hormone Therapy Medicine 

A substudy of the WHI observational study exploring inherited platelet variants and their 

interactions with hormone therapy to identify genetic predictors of coronary heart disease events 

in women. 

Multiproject Prevalence & Progression of 

Subclinical Atherosclerosis 
 

61 

A determination of the extent to which diminishing ovarian function affects vascular function and 

accelerates the development of atherosclerosis in the coronary arteries, aorta, and carotid 

arteries.

Representative FY 2004 Publications 

1. Bittner, V et al. Remnant-like lipoproteins, hormone therapy, and angiographic 

and clinical outcomes: the Women=s Angiographic Vitamin and Estrogen Trial. 

Am Heart J 2004 Aug;148(2):293-99. 

2. Wildman, RP et al. A dietary and exercise intervention slows menopauseassociated progression of subclinical atherosclerosis as measured by intima-media 

thickness of the carotid arteries. J Am Coll Cardiol 2004 Aug 4;44(3):579-85. 

3. Howard, BV et al. Postmenopausal hormone therapy is associated with 

atherosclerosis progression in women with abnormal glucose tolerance. 

Circulation 2004 Jul 13;110(2):201-06. 

4. The Women=s Health Initiative Steering Committee. Effects of conjugated equine 

estrogen in postmenopausal women with hysterectomy: the Women=s Health 

Initiative randomized controlled trial. JAMA 2004 Apr 14;291(14):1701-1712. 

5. Olson, MB et al. Hormone replacement, race, and psychological health in 

women: a report from the NHLBI-sponsored WISE study. J Womens Health 

2004 April;13(3):325-32. 

6. Brownley, KA et al. Cardiovascular effects of 6 months of hormone replacement 

therapy versus placebo: differences associated with years since menopause. Am 

J Obstet Gynecol 2004 Apr;190(4):1052-58. 

7. Chlebowski, RT et al. Estrogen plus progestin and colorectal cancer in 

postmenopausal women. N Engl J Med 2004 Mar 4;350(10):991-1004. 

8. Zhang, Y et al. Associations of postmenopausal hormone therapy with markers of 

hemostasis and inflammation and lipid profiles in diabetic and nondiabetic 

American Indian women: the Strong Heart Study. J Womens Health 2004 

Mar;13(2):155-63. 

9. Waters DD et al. Women=s Ischemic Syndrome Evaluation: current status and 

future research directions: report of the National Heart, Lung, and Blood Institute 

workshop. Circulation 2004 Feb 17;109(6):e53-55. 
 

62 

• 

10. Hsia J et al. Estrogen plus progestin and the risk of peripheral arterial disease: 

the Women=s Health Initiative. Circulation 2004 Feb 10;109(5):620-26. 

11. Hersh, AL et al. National use of postmenopausal hormone therapy: annual trends 

and response to recent evidence. JAMA 2004 Jan 7;291(1):47-53. 

12. Girdler SS et al. Transdermal versus oral estrogen therapy in postmenopausal 

smokers: hemodynamic and endothelial effects. Obstet Gynecol 2004 

Jan;103(1):169-80. 

13. Simkin-Silverman LR et al. Lifestyle intervention can prevent weight gain during 

menopause: results from a 5-year randomized clinical trial. Ann Behav Med 

2003 Dec;26(3):212-220. 

14. Anderson, GL et al. Effects of estrogen plus progestin on gynecologic cancers 

and associated diagnostic procedures: the Women=s Health Initiative randomized 

trial. JAMA 2003 Oct 1;290(13):1739-48. 

15. Cauley, JA et al. Effects of estrogen plus progestin on risk of fracture and bone 

mineral density: the Women=s Health Initiative randomized trial. JAMA 2003 

Oct 1;290(13):1729-38. 

16. Farag, NH et al. Autonomic responses to psychological stress: the influence of 

menopausal status. Ann Behav Med 2003 Oct;26(2):134-38. 

Public Education 

The Postmenopausal Hormone Therapy Fact Sheet explains research findings, issues 

related to long- and short-term hormone use, risk factors for heart disease, and 

alternatives to hormone therapy. For a copy, visit 

www.nhlbi.nih.gov/health/women/pht_facts.htm. 

• The Heart Truth, a national awareness campaign, targets women ages 40 to 60 and 

encourages them to take their heart health seriously, talk to their doctors about it, and 

take steps to reduce their risk. For more information, visit the campaign=s Web site at 

www.nhlbi.nih.gov/health/hearttruth. 
 

63 

National 

Institute on 

Aging 

(NIA) 
 

64 

NIA FY 2003-2004 Science Advances and Key Activities on 

Menopause 

Advances

Decreased sensitivity to estrogen may help explain menopausal changes. A new study suggests that 

age-related changes in how the brain responds to the female sex hormone estrogen may be involved in a 

woman’s transition through menopause. The study provides new clues about hormonal influences on hot 

flashes and night sweats experienced by some women in the menopause transition. 

A new rodent model of the menopause. Traditionally, researchers have removed the ovaries in rodent 

models in order to explore biologic processes underlying the associations between “menopause” and 

pathophysiology of tissues and organs associated with postmenopausal health problems, such as 

osteoporosis and cardiovascular disease. However, NIA- supported investigators have recently developed 

a new model in which the animal retains its ovaries while accelerating loss of ovarian follicles, leaving 

the hypothalamic-pituitary-ovarian axis (the interdependent relationship between the ovaries and brain 

that regulates hormonal events such as menstruation) intact. This provides a new means to study the 

impact of follicle loss on the pathophysiology of various postmenopausal health problems and conditions. 

Possible new mechanism for hot flashes. Although some 80 percent of women approaching menopause 

experience hot flashes, the symptoms' physiological trigger has yet to be identified. Results of a recent 

study of menopausal women suggest that conditions of fasting and low blood glucose may be factors the 

increase the likelihood of hot flashes. Interventions aimed at maintaining blood glucose may show 

promise in reducing the burden of hot flashes. 

 

Women who experience premenstrual syndrome (PMS) are more likely to experience menopauserelated symptoms. Although the PMS improves during the menopausal transition, investigators recently 

found that women who reported PMS when they were premenopausal are at greater risk of menopausal 

hot flushes, depressed mood, poor sleep, and decreased libido. 

The menopause transition and depression. The role of the transition through the menopause and 

altered levels of reproductive hormone levels on depressed mood is controversial. To evaluate the role of 

changes in menopausal status and reproductive hormones levels on depressed mood, assessments were 

conducted in a sample of African American and white women. Researchers found that depressive 

symptoms increased during the menopause transition but decreased thereafter in postmenopausal women. 

The association of depressive symptoms with changes in reproductive hormones supports the hypothesis 

that the changing hormonal milieu contributes to disturbances in mood during transition to menopause. 

Regular physical activity during the menopause transition can counter age-related weight gain.

During the transition from premenopause to postmenopause, many women experience loss of lean mass 

and gains in weight, fat mass, and central fat deposition. However controversy exists regarding the 

degree to which the increases in total fat and central fat over the course of the menopausal transition are 

the result of menopause itself or a consequence of chronologic aging. To address this question, the 

investigators examined the potential role of aging, menopausal status, and physical activity on weight and 

waist circumference in 3,064 racially/ethnically diverse women aged 42-52 years at baseline who were 

participating in the Study of Women's Health Across the Nation (SWAN). Self-reported physical activity 

in various domains, including sports/exercise, household/caregiving and daily routine (defined as walking 

or biking for transportation) was assessed. Their findings suggest that, although midlife women tend to 

experience increases in weight and waist circumference over time, maintaining or increasing participation 

in regular physical activity can contribute to prevention or moderation of those gains. [Co-funded by 

OWRH] 
 

65 

Reproductive hormone levels vary markedly by race/ethnicity, body mass and stage of the 

menopause transition as women age. The menopausal transition is characterized by a progressive rise in 

serum follicle stimulating hormone (FSH) associated with a decrease in serum estradiol (E2) levels. In the 

first study of cross-sectional ethnic differences in levels of reproductive hormones in midlife women, 

investigators assayed E2 and FSH levels in the early follicular phase of a spontaneous menstrual cycle in 

three consecutive annual visits during the SWAN study. They found that: 

 

• Serum E2 concentrations decreased significantly with age, with a steeper decline at higher ages. 

• FSH concentrations increased significantly with age, with a steeper increase at higher ages. 

• Similar patterns in the decline of E2 and the increase in FSH with age were found across ethnic 

groups, but the levels of these hormones differed by race/ethnicity. 

• Over time, Chinese and Japanese women had lower E2 concentrations but similar FSH levels, 

compared to Caucasian women. 

• African American women had higher FSH concentrations but comparable E2 levels with those of 

Caucasian women. 

• These ethnic differences in E2 and FSH were independent of menopausal status (i.e., whether the 

woman was pre-or perimenopausal). 

• Increasing body mass index (BMI) was associated with decreasing concentrations of E2 among 

premenopausal and early perimenopausal women but was associated with increasing concentrations of 

E2 among late perimenopausal and postmenopausal women. 

• Increasing BMI was also associated with decreasing concentrations of FSH, with the effect of BMI 

becoming larger as women transitioned through menopause. 

Ethnic differences in the relationships between E2 and FSH over time suggest the role of race/ethnicity as 

a potentially important determinant of changing pituitary-ovarian relationships between E2 and FSH with 

aging. These findings also underscore the importance of BMI as a determinant of hormone levels and 

raise the possibility that ethnic differences in menopausal symptoms and health outcomes may be related, 

at least in part, to ethnic differences in reproductive hormones and/or their interrelationships. [Co-funded 

by OWRH] 

Memory loss is not an inherent outcome of the menopause transition. Previous studies have 

found increased self-reporting of forgetfulness during the menopausal transition. These findings have 

been consistent with the widespread belief that the hormonal changes culminating in, or due to, the 

menopause produce predominantly deleterious global changes in health status and/or accelerate the 

aging process(es). However, investigators on the Study of Women’s Health Across the Nation, a 

study of the menopausal transition, observed small but significant improvements in cognitive scores 

with aging after adjusting for ethnicity, education, income and self-reported health. Significant 

improvements in working memory and perceptual speed were observed from pre-menopause through 

later stages of menopause. In women who became post-menopausal, working memory improved but 

perceptual speed declined. Although additional follow-up is needed, many will find the results of the 

study reassuring, in that they provide no evidence for a menopause-related decline in mental function 

that had been suggested based on earlier studies. [Co-funded by ORWH] 

Activities

January 20, 2004: Workshop on Assessing and Improving Measures of Hot Flashes. NIA 

participated in this workshop, which was convened by NCCAM, in collaboration with the Office of 

Research on Women’s Health (ORWH), NIBIB, NCI, NHLBI, NICHD, the Office of Extramural 

Research (OER), and the Office of Behavioral and Social Sciences Research (OBSSR). The objectives of 

this workshop included assessing our understanding of the physiological and endocrine parameters 

associated with hot flashes, the self-reported experience of hot flashes, and the quality of existing 
 

66 

subjective and objective measures of hot flashes, and the barriers and opportunities to improve these 

measures. 

May 26-27, 2004: The Biology of the Perimenopause: Impact on Health and Aging. The 1.5 day 

workshop consisted of 4 plenary lectures (Premenopausal protection against chronic diseases of aging: 

rethinking the paradigms; Neurobiology of ovarian steroids; Dynamics of the female reproductive system 

and changes with aging; Relating aging and outcomes of menopause) and 6 broader discussion sessions 

(animal models, adipose tissue, immune system, bone, cardiovascular, and cognition and brain function). 

The presentations and discussion explored the hypothesis that changes in hypothalamic-pituitary-ovarian 

(H-P-O) axis hormones (estrogen, androgen, progesterone, inhibin/activin, gonadotropins, etc.) and 

hormonal dynamics across the menopausal transition in middle-aged women increase the risk for disease 

and other pathophysiologic conditions in non-reproductive end organs and systems. Co-funded by 

ORWH. 

September 28-29, 2004: Bench to Bedside: Estrogen as a Case Study. While the majority of studies 

published to date in animal models indicate that estrogen’s effects are beneficial, clinical studies have 

provided inconsistent results. This workshop was held to examine the reasons why basic science, 

epidemiological, and some clinical studies have had different outcomes than clinical trials. The workshop 

had four objectives: 

• To define and examine the discrepancies between the findings of the Women’s Health Initiative 

(WHI)/ Women’s Health Initiative Memory Study (WHIMS) on brain and cognitive function and the 

basic and longitudinal/epidemiological studies 

• To examine the effects of estrogens on brain and cognitive function as they relate to aging 

• To determine what is known and what information we would need to obtain that would determine 

whether additional hormone “interventions” could be developed 

• To determine what lessons we have learned from studies on estrogen that will help in designing 

clinical trials for other classes of drugs. 

An RFA, “Biology of the Perimenopause: Impact on Health and Aging,” has been released and will be 

funded in 2006. The goal of this RFA is solicit applications for research studies to better understand 

underlying biologic mechanisms associated with the increased risk for, or decreased protection leading to, 

health problems and conditions associated with the menopausal process in middle-aged women. 

NIA is collaborating with the National Center for Complementary and Alternative Medicine on a clinical 

trial called “Does Menopause Matter?” The purpose of this study is to follow a woman’s progression 

through menopause in order to examine the effects on health-related quality of life and use of health care 

resources, and to understand how women are using alternative therapies. Recruitment has not yet begun, 

but ultimately 720 women are expected to participate.
 

67 

Research Advance(s)

Reproductive hormone levels vary markedly by race/ethnicity, body mass and stage of the 

menopause transition as women age. The transition from active reproductive potential to reproductive 

senescence in women is characterized by a progressive rise in serum follicle stimulating hormone (FSH) 

associated with a decrease in serum estradiol (E2) levels. However, no study has investigated crosssectional ethnic differences in levels of reproductive hormones in midlife women, let alone longitudinal 

changes associated with the menopause transition. In order to determine whether there are differences in 

hormones that can be explained by host factors, E2 and FSH were assayed in serum collected primarily in 

the early follicular phase of a spontaneous menstrual cycle in three consecutive annual visits. At the 

baseline visit, 46.2% of the women were classified as being early perimenopausal, with the remaining 

being premenopausal. By the second follow-up visit, 5.5% of the women in that cohort were 

postmenopausal, 66.8% were early perimenopausal, 8.3% were late perimenopausal, and 19.4% remained 

premenopausal. Serum E2 concentrations decreased significantly with age (figure A), with a steeper 

decline at higher ages. FSH concentrations increased significantly with age (figure B), with a steeper 

increase at higher ages. Similar patterns in the decline of E2 and the increase in FSH with age were found 

across ethnic groups, but the levels of these hormones differed by race/ethnicity. Specifically, over time, 

Chinese and Japanese women had lower E2 concentrations but similar FSH levels, compared to 

Caucasian women, whereas African American women had higher FSH concentrations but comparable E2 

levels with those of Caucasian women. 

These ethnic differences in E2 and FSH were independent of menopausal status. Interestingly, the effect 

of body mass index (BMI) on serum E2 and FSH levels varied by menopausal status. Increasing BMI was 

associated with decreasing concentrations of E2 among premenopausal and early perimenopausal women 

but was associated with increasing concentrations of E2 among late perimenopausal and postmenopausal 

women. Increasing BMI was also associated with decreasing concentrations of FSH, with the effect of 

BMI becoming larger as women transitioned through menopause. 

Ethnic differences in the relationships between E2 and FSH over time suggest the role of race/ethnicity as 

a potentially important determinant of changing pituitary-ovarian relationships between E2 and FSH with 

aging. These findings also underscore the importance of BMI as a determinant of hormone levels and 

raise the possibility that ethnic differences in menopausal symptoms and health outcomes may be related, 

at least in part, to ethnic differences in reproductive hormones and/or their interrelationships. [The 

SWAN Investigators; UO1 AG12505; UO1 AG12535;U01 NR0406; U01 AG12531, UO1 AG12539, 

U01 AG12546, U01 AG12553, U01 AG12554, UO1 AG12495]
 

68 

Randolph JF Jr, Sowers M, Bondarenko IV, Harlow SD, Luborsky JL, Little RJ. Change in 

estradiol and follicle-stimulating hormone across the early menopausal transition: effects of 

ethnicity and age. J Clin Endocrinol Metab. 2004;89(4):1555-61. 

Regular physical activity during the menopause transition can counter age-related weight 

gain. During the transition from premenopause to postmenopause, many women experience loss 

of lean mass and gains in weight, fat mass, and central fat deposition. However controversy 

exists regarding the degree to which the increases in total fat and central fat over the course of 

the menopausal transition are the result of menopause itself or a consequence of chronologic 

aging. To address this question, the investigators examined the potential role of aging, 

menopausal status, and physical activity on weight and waist circumference in 3,064 

racially/ethnically diverse women aged 42-52 years at baseline who were participating in the 

Study of Women's Health Across the Nation (SWAN), an observational study of the menopausal 

transition. Self-reported physical activity in various domains, including sports/exercise, 

household/caregiving and daily routine (defined as walking or biking for transportation) was 

assessed. Over 3 years of follow-up, mean weight increased by 2.1 kg or 3.0% and mean waist 

circumference increased by 2.2 cm or 2.8%. However, changes in menopausal status were not 

significantly associated with weight gain or with increases in waist circumference. Importantly, 

a one-unit increase in reported level of sports/exercise (on a scale of 1-5) was related to a highly 

significantly decrease of 0.32 kg in weight and an absence of increases in waist circumference. 

Weight and waist circumference changes were likewise related to changes in daily routine 

physical activity (biking and walking for transportation and less television viewing). These 

findings suggest that, although midlife women tend to experience increases in weight and waist 

circumference over time, maintaining or increasing participation in regular physical activity can 

contribute to prevention or moderation of those gains. [The SWAN Investigators; UO1 

AG12505; UO1 AG12535;U01 NR0406; U01 AG12531, UO1 AG12539, U01 AG12546, U01 

AG12553, U01 AG12554, UO1 AG12495] 

Sternfeld B, Wang H, Quesenberry CP Jr, Abrams B, Everson-Rose SA, Greendale GA,et al. 

Physical activity and changes in weight and waist circumference in midlife women: findings 

from the Study of Women's Health Across the Nation. Am J Epidemiol. 2004;160(9):912-22. 

The menopause transition and depression. The role of the transition through the menopause 

and altered levels of reproductive hormone levels on depressed mood is controversial. To 

evaluate the role of changes in menopausal status and reproductive hormones levels on depressed 

mood, assessments were conducted in a randomly identified, population-based, sample of 218 

African American and 218 white women aged 35 to 47 years with regular menstrual cycles and 

no hormonal or psychotropic medication use. There were six assessment periods and 12 blood 

draws during a 4-year study interval of these midlife women participants in the Penn Ovarian 

Aging Study. 

After adjustment for other predictors of depression (history of depression, severe premenstrual 

syndrome, poor sleep, age, race, and employment status), there was an increased likelihood of 

depressive symptoms during the menopause transition and a decreased likelihood after 

menopause. The likelihood of depressive symptoms decreased for individuals with a rapidly 

increasing follicle-stimulating hormone (FSH) profile and also decreased with age compared 
 

69 

with premenopausal women. It was also observed that women with increasing estrogen profiles 

(which occur during the early transition to menopause)reported more depressive symptoms. It 

was concluded that the depressive symptoms assessed in this study increased during the 

menopause transition but decreased thereafter in postmenopausal women. The association of 

depressieve symptoms with changes in reproductive hormones supports the hypothesis that the 

changing hormonal milieu contributes to dysphoric (disturbances in) mood during transition to 

menopause. [E. Freeman, U Pennsylvania, Philadelphia; R01 AG12745] 

Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and 

menopausal status as predictors of depression in women in transition 

to menopause. Arch Gen Psychiatry. 2004;61(1):62-70. 

Title: Decreased Sensitivity in the Brain to Estrogen May Help Explain Menopausal Changes 

Background: There is a marked decline in estrogen (E) levels after the final menstrual cycle 

and the start of the postmenopausal period. However, earlier, in their forties, as women enter 

the menopause transition and approach their final menstrual period (FMP), changes in menstrual 

cycle regularity and hormonal patterns occur as does an increase in the reporting of symptoms 

such as hot flashes and night sweats. The NIH-supported Study of Women’s Health Across the 

Nation (SWAN), a multi-site survey of 3300 women who were 42-52 years of age when they 

were enrolled in the study in 1996 follows the biological, physical and hormonal changes 

experienced by women as they approach and traverse the menopause transition. 

Advance: In a substudy that involved the daily collection of urine samples and questionnaire 

data about symptoms, different patterns of hormone fluctuations were observed in women who 

did not ovulate. In one group of women, there was a surge of luteinizing hormone (LH), an 

appropriate response to the rise in E levels occurring in early part of the menstrual cycle. In the 

second, the same increases in E were not associated with an LH surge. In the third group, 

although E levels in the early part of the cycle were similar to levels in groups 1 and 2, E levels 

did not show similar increases as the cycle progressed, there was no LH surge and LH levels 

were higher for most of the cycle. The hormonal patterns in groups 2 and 3 suggest different 

kinds of reduced sensitivity of estrogen in the brain. Interestingly, the women in the third group 

had significantly more hot flashes and night sweats than those in the other two groups. 

Implications: These findings 1) suggest that a specific hormonal pattern linked to increased hot 

flashes reflects alterations in the sensitivity of the brain to estrogen and 2) provide new clues 

about hormone influences on hot flashes and night sweats as women approach menopause. A 

better understanding of the role of changing levels of, and responses to, hormones such as E and 

LH in causing menopause-related symptoms is needed to develop new approaches for managing 

symptoms occurring during the menopause transition. 

Citation: 

Weiss G, Skurnick JH, Goldsmith LT, Santoro NF, Park SJ. Menopause and hypothalamicpituitary sensitivity to estrogen. JAMA. 2004 Dec 22;292(24):2991-6
 

70 

 

 

Decreased sensitivity in the brain to estrogen may help explain 

menopausal changes (Public release date: 21-Dec-2004)

A new study suggests that age–related changes in how the brain responds to the female sex 

hormone estrogen may be involved in a woman's transition through menopause. The study 

provides new clues about hormonal influences on hot flashes and night sweats experienced by 

some women in the menopause transition. 

The findings are reported in the December 22/29, 2004, Journal of the American Medical 

Association* and are based on data from the Study of Women's Health Across the Nation 

(SWAN), a multi-site survey of women going through the menopause transition. This study is 

funded by the National Institutes of Health. 

"Throughout a woman's reproductive life, there are not only age-related changes in estrogen 

levels, but also differences in how her body responds to given levels of estrogen. Researchers 

have been trying to understand how and why these changes take place," says Sherry Sherman, 

Ph.D., project director of the SWAN study, National Institute on Aging (NIA). "Hormone 

patterns found in this study could mean that, with age, a part of a woman's brain which regulates 

reproductive hormone levels may become less sensitive to estrogen. Other study findings suggest 

that the decreases in sensitivity can lead to significantly increased hot flashes and night sweats." 

The analysis was led by Gerson Weiss, M.D., New Jersey Medical School at the University of 

Medicine and Dentistry of New Jersey (UMDNJ), who with his colleagues from the SWAN 

study reported the findings. UMDNJ is one of seven SWAN sites supported by the NIA, the 

National Institute of Nursing Research, and the Office of Research on Women's Health, all parts 

of the National Institutes of Health (NIH) at the Department of Health and Human Services. 

SWAN follows more than 3,300 women, ages 42-52 at the beginning of the study in 1995, as 

they experience the changes associated with approaching menopause. The data for this report 

came from the Daily Hormone Study, a substudy that involves the daily collection of urine 

samples and completion of a questionnaire about symptoms, for a period of one menstrual cycle 

or a maximum of 50 days (if no menstruation occurs). 

Through this sampling, the study characterized the fluctuations in hormones such as estrogen, 

which is produced by the ovary, and fluctuations in other hormones such as luteinizing hormone 

(LH), which is produced by the pituitary, a gland at the base of the brain. These reproductive 

hormones are needed for normal menstrual cycles and to prepare the body for pregnancy. 

In this study, the hormone levels in some of these middle-aged women reflected a likely 

insensitivity to estrogen in the brain. The data showed three different patterns of hormone 

fluctuations in women who did not ovulate: the first group of women had a surge of LH--an 

"appropriate" response to increases in estrogen. In a second group, the same increases in estrogen 

were not associated with a surge in LH. In the third group, estrogen levels early in the cycle were 

similar to those of groups 1 and 2, but, unlike those two groups, did not show further increases. 

The LH levels in this group did not show a surge and were higher for most of the cycle than in 

the other groups. The hormonal patterns in groups 2 and 3 suggest different kinds of reduced 

sensitivity to estrogen (or abnormal estrogen "feedback") in the brain. 

Interestingly, the women in the third group had significantly more hot flashes and night sweats 

than women in the other two groups. These findings suggest that the hormonal pattern associated 
 

71 

with increases in symptoms reflects alterations in the sensitivity to estrogen in the brain. 

Additional follow-up of the women as they experience their final menstrual period and become 

postmenopausal is needed to further clarify the hormonal changes underlying the menopause 

transition as well as those causing hot flashes. 

The findings in these women are the first to describe hormone patterns reflecting changes in 

responses to estrogen and are consistent with previous studies in other mammals that have 

described similar central nervous system insensitivity to estrogen with aging. A better 

understanding of the role of changing responses to reproductive hormones including estrogen in 

causing menopause-related symptoms is needed to develop new approaches for managing 

symptoms occurring at this time. 

Because of the need to identify treatment options for women experiencing symptoms such as hot 

flashes during the menopause transition, the NIA and NIH's Office of Medical Applications of 

Research are sponsoring a State-of-the Science Conference on Management of MenopauseRelated Symptoms, March 21-23, 2005, in Bethesda, MD. This meeting will bring together 

experts in the field who will present information on the biology of the menopause transition, 

common symptoms during this time, and possible treatments to an independent panel. This panel 

will prepare a state-of-the-science statement to provide guidance to women and their doctors, as 

well as to suggest future research directions. 

### 

Further information is available at www.consensus.nih.gov. 

The NIA, www.nia.nih.gov, conducts and supports research on aging and age-related diseases. 

For more information on menopause, please visit the NIH's Menopausal Hormone Therapy page 

at http://www.nih.gov/PHTindex.htm. To request a free copy of the NIA brochure, Menopause: 

One Woman's Story, Every Woman's Story, visit www.niapublications.org, or call 1-800-222-

2225. The National Institute of Nursing Research, http://ninr.nih.gov, supports clinical and basic 

research in order to provide a scientific basis for the care of individuals across the lifespan. The 

Office of Research on Women's Health, http://www4.od.nih.gov/orwh/, works to advance 

research activities on behalf of all women. 

*Weiss, G, Skurnick, JH, Goldsmith, LT, Santoro, NF, and Park, SJ, Menopause and 

Hypothalamic-Pituitary Sensitivity to Estrogen. JAMA. 2004. 

Grant Number PI Name Project Title 

Menopause 

1K23AG024254-01 HESS, RACHEL Does Menopause Matter?

1R01AG024154-01 HODIS, HOWARD Biologic Response of Menopausal Women to 17B-Estradiol

5R01AG021948-02 HOYER, PATRICIA Ovary Intact Murine Model for Menopause

5R01AG014124-08 YOUNG, TERRY Menopause and Midlife Aging Effects on Sleep Disorders

5R01AG019361-03 GOLD, ELLEN Sleep during the peri-menopause in a multi-ethnic cohort

5R01AG013204-08 VOYTKO, MARY LOU Cognition and Estrogen in Menopause:A Monkey Model

5R01AG012745-09 FREEMAN, ELLEN 

EPIDEMIOLOGIC STUDY OF THE LATE 

REPRODUCTIVE YEARS
 

72 

5R01AG019362-03 HALL, MARTICA Sleep During the Perimenopause in a Multi-Ethnic Cohort

5R01AG021543-02 HARLOW, SIOBAN Staging Reproductive Aging in Five Cohort Studies

5R01AG019363-03 KRAVITZ, HOWARD Sleep During the Perimenopause in a Multi-Ethnic Cohort

1Z01AG000293-15 METTER, EARL Biochemical Parameters Of Bone Metabolism Age

5R01AG020162-02 MOORMAN, PATRICIA Ovarian Failure Among Hysterectomized Women

5R01AG009214-12 RANCE, NAOMI Reproductive Aging and the Human Hypothalamus

5R01AG019360-03 SOWERS, MARYFRAN Sleep During the Perimenopause in a Multi-Ethnic Cohort

5R37AG021665-02 SOWERS, MARYFRAN Estrogen, Metabolism, Menopause, and Health Outcomes

2U01AG012531-11A1 FINKELSTEIN, JOEL Study of Women's Health Across the Nation - III

2U01AG012554-11A1 GOLD, ELLEN Study of Women's Health Across the Nation III--UC Davis

5R01AG018408-05 GOLDBERG, ANDREW 

MENOPAUSE, LPL GENOTYPE AND METABOLISM 

AFTER WEIGHT LOSS

5R01AG018198-05 KOHRT, WENDY 

MODULATION OF VISCERAL FAT BY ESTROGENS 

AFTER MENOPAUSE

2U01AG012546-11A1 MATTHEWS, KAREN Womens Health Across the Nation

2U01AG012495-11A1 MCCONNELL, DANIEL Study of Women's Health Across the Nation-Endocrine Lab

5R01AG017057-04 NEWTON, KATHERINE 

ALTERNATIVE THERAPIES FOR MENOPAUSE: A 

RANDOMIZED TRIAL

5R01AG017104-05 SOWERS, MARYFRAN 

FUNCTIONAL STATUS AND THE MENOPAUSAL 

TRANSITION

5R01AG020082-03 VITIELLO, MICHAEL PROGESTERONE AND SLEEP IN OLDER WOMEN

5R01AG015857-05 CHAUDHURI, GAUTAM 

ROLE OF NO AND ESTRADIOL IN AGING AND 

ATHEROGENESIS

1R03AG023251-01A1 DEMERATH, ELLEN Telomere Length as a Marker of Cardiovascular Aging

2U01AG012539-11A1 GREENDALE, GAIL Study of Woman's Health Across the Nation - UCLA

1R01AG023139-01A1 KUEHL-KOVARIK, MARY Functional changes in GnRH neurons with age

1Z01AG000647-07 NAGARAJA, RAMAIAH Genes Assoc With Ovarian Develop /Premature Ovarian Fail

5R01AG021476-02 NEWHOUSE, PAUL Estrogen Effects on Cholinergic Function in Older Women

5R01AG017578-05 OBERMEYER, CARLA 

THERAPEUTIC DECISIONS AT MENOPAUSE--A 

MULTISITE STUDY

2U01AG012505-11A1 POWELL, LYNDA Study of Women's Health Across the Nation

2P01AG004875-210001 RIGGS, B. LAWRENCE 

PATHOPHYSIOLOGY OF OSTEOPOROSIS IN AGING 

WOMEN

2U01AG012535-11A1 SANTORO, NANETTE SWAN-Study of Women's Health Across the Nation-N.J.site
 

73 

1R03AG023330-01 SINGH, MEHARVAN Progesterone, GABA Receptors and Cell Survival

5U01AG017719-05 SOWERS, MARYFRAN SWAN REPOSITORY

2U01AG012553-10A1 TYRRELL, KIM Study/Women/Health Across Nation III/Coordinating Center

5K01AG019630-03 VAN PELT, RACHAEL 

ESTROGEN, INSULIN AND REGIONAL LIPOLYSIS IN 

OLDER WOMEN

5U01AG021382-03 ZELINSKI-WOOTEN, MARY Ovarian Aspects of Caloric Restriction

5R01AG021593-02 AVIV, ABRAHAM Telomeres and Vascular Aging

1R03AG023925-01 

BIMONTE-NELSON, 

HEATHER Progesterone, aging, and memory loss

5K12AG019247-03 CARNES, MARY 

WOMEN'S HEALTH AND AGING: CLINICAL 

SCIENTIST DEVELOPMENT

1F32AG023430-01A1 DUMAS, JULIE Estrogen and Cognition In Postmenopausal Women

5R01AG017170-06 ELLIOT, SHARON Estrogen Deficiency and REnal Disease in Aging Women

5R01AG018400-04 FLAWS, JODI Risk Factors for Hot Flashes in Mid-Life

5R37AG005233-17 FREEDMAN, ROBERT 

BEHAVIORAL TREATMENT OF MENOPAUSAL HOT 

FLASHES

5R01AG020116-02 GOLDBERG, ANDREW Race, Lipoprotein Lipase and Obesity after Menopause

5R01AG015955-06 GORODESKI, GEORGE Estrogen and Aging effects on Transvaginal Transpoet

5R01AG013241-06 HALL, JANET Aging and the Hypothalamic-Pituitary Reproductive Axis

5R01AG018798-04 HODIS, HOWARD 

ESTROGEN IN THE PREVENTION OF 

ATHEROSCLEROSIS TRIAL

5R01AG015345-07 INSOGNA, KARL Role of IL-6 in PTH-Induced Bone Resorption

3R01AG018198-05S1 KOHRT, WENDY 

MODULATION OF VISCERAL FAT BY ESTROGENS 

AFTER MENOPAUSE

2P01AG004875-210002 MELTON, L. JOSEPH III% 

RISK FACTORS FOR HIP FRACTURES AMONG THE 

ELDERLY

5R01AG020583-03 NICKLAS, BARBARA Excercise and Regional Fat Metabolism after Menopause

3R01AG020583-03S1 NICKLAS, BARBARA Excercise and Regional Fat Metabolism after Menopause

5R01AG020263-03 RICKLEFS, ROBERT Demographic Aging in Captive Birds and Mammals

1T32AG023475-01 ROSSETTI, LUCIANO Training in Aging Research

3R01AG013204-07S1 VOYTKO, MARY LOU Cognition and Estrogen in Menopause:A Monkey Model

5P01AG017164-05 WISE, PHYLLIS 

FEMALE REPRODUCTIVE AGING: THE ROLE OF 

ESTROGEN

Aging Women

2T32AG000265-06 CARNES, MARY Women's Health & Aging:Research and Leadership Training
 

74 

5R01AG013241-06 HALL, JANET Aging and the Hypothalamic-Pituitary Reproductive Axis

5R01AG021543-02 HARLOW, SIOBAN Staging Reproductive Aging in Five Cohort Studies

5R01AG017042-05 ANVERSA, PIERO AGE, GENDER AND THE FAILING HEART

5R37AG019905-04 FRIED, LINDA Pathogenesis of physical disability in Aging women

1Z01AG000191-08 RESNICK, SUSAN Neuroimaging Predictors Of Cognitive Change And Response

5K23AG019161-03 CAPPOLA, ANNE Androgens, Myostatin, and Sarcopenia in Older Women

5K12AG019247-03 CARNES, MARY 

WOMEN'S HEALTH AND AGING: CLINICAL 

SCIENTIST DEVELOPMENT

5R01AG017170-06 ELLIOT, SHARON Estrogen Deficiency and REnal Disease in Aging Women

5R01AG012745-09 FREEMAN, ELLEN 

EPIDEMIOLOGIC STUDY OF THE LATE

REPRODUCTIVE YEARS

5U01AG020487-04 HOLLOSZY, JOHN Caloric Restriction and Aging in Humans

5R01AG018843-02 JANOWSKY, JERI Mechanisms for sex steroid effects on cognition in aging

5P01AG018911 CACIOPPO, JOHN Social Isolation, Loneliness, Health, and Aging Women

2P01AG004875-21 KHOSLA, SUNDEEP Physiology of Bone Metabolism in an Aging Population

1Z01AG000908-04 LING, SHARI Inflammation and Osteoarthritis of the Knee

2U01AG012495-11A1 MCCONNELL, DANIEL Study of Women's Health Across the Nation-Endocrine Lab

1Z01AG000802-13 NAJJAR, SAMER Effects Of Age And Conditioning Status On Rest And Exerc

2P01AG004875-210001 RIGGS, B. LAWRENCE% 

PATHOPHYSIOLOGY OF OSTEOPOROSIS IN AGING 

WOMEN

5R01AG014799-08 VELDHUIS, JOHANNES THE AGING GH AXIS IN POSTMENOPAUSAL WOMEN

5R01AG015857-05 CHAUDHURI, GAUTAM 

ROLE OF NO AND ESTRADIOL IN AGING AND 

ATHEROGENESIS

5R01AG017496-05 DOTY, RICHARD 

POSTMENOPAUSAL ESTROGEN INFLUENCES ON 

OLFACTION

5R01AG021106-02 FUKAGAWA, NAOMI Age-related changes in glutathione synthesis

1Z01AG007360-01 GURALNIK, JACK Single Nucelotide Polymorphisms and Disability

5R01AG007004-15 KENNEY, W. AGE AND CONTROL OF HUMAN SKIN BLOOD-FLOW

2P01AG004875-210006 KHOSLA, SUNDEEP 

PATHOPHYSIOLOGY OF OSTEOPOROSIS IN AGING 

MEN

1Z01AG000293-15 METTER, EARL 

Biochemical Parameters Of Bone Metabolism--age And Sex 

C

1Z01AG000636-15 METTER, EARL Study Of Physical Activities In The Blsa

5K01AG020683-03 MOREAU, KERRIE HRT and Exercise Effects on Central Arterial Compliance

5R01AG021500-02 ROTH, STEPHEN Genetic Architecture of Aging Skeletal Muscle

5R01AG018409-04 TRAPPE, SCOTT Single Muscle Fiber Contractile Properties With Aging

5P01AG011412-090009 VAN CAUTER, EVE 

"IMPACT OF A SLEEP DEBT IN MIDDLE-AGED AND 

OLDER ADULTS"
 

75 

5R01AG021918-02 YAFFE, KRISTINE Sex Hormones, Related Polymorphisms & Cognitive Decline

5R01AG014124-08 YOUNG, TERRY Menopause and Midlife Aging Effects on Sleep Disorders

5R01AG017973-04 ADLER, SHELLEY 

OLDER PATIENT-PHYSICIAN-ALTERNATIVE HEALER 

RELATIONSHIPS

5R01AG020521-02 BENZ, CHRISTOPHER Biology of Breast Cancers Arising in Older Women

1R03AG023925-01 BIMONTE-NELSON, HEATHER Progesterone, aging, and memory loss

5R01AG019825-03 CARLSON, MICHELLE Cognitive Pathways to Disability

7U01AG018197-06 CUMMINGS, STEVEN OSTEOPOROTIC FRACTURES IN MEN

5T32AG020506-03 DISTERHOFT, JOHN Mechanisms of Aging and Dementia Training Program

5R01AG011703-11 FRIED, LINDA 

RISK FACTORS FOR PHYSICAL DISABILITY IN AGING 

WOMEN

5R01AG017880-03 GREENBLATT, DAVID CYP3A Function in Aging AfricanAmericans

1R01AG022551-01A1 GRIGSBY, JAMES Chemotherapy & Cognition in Older breast Cancer Patients

1Z01AG007310-03 GURALNIK, JACK Pain And Physical Functioning in Older Women

5R01AG018336-04 HURLEY, BERNARD 

GENE EFFECTS ON STRENGTH RESPONSES TO AGE 

AND EXERCISE

1R03AG023860-01 KANG, JAE Plasma Markers of Dietary Intervention to Delay Cogniti

5R01AG019327-04 KNOWLTON, ANNE 

AGING, ESTROGEN, HSPS AND MYOCARDIAL 

ISCHEMIA

2U01AG012546-11A1 MATTHEWS, KAREN Womens Health Across the Nation

5K08AG021631-02 NEUNER, JOAN Adoption of osteoporosis screening in older women

5R01AG021476-02 NEWHOUSE, PAUL Estrogen Effects on Cholinergic Function in Older Women

2U01AG012505-11A1 POWELL, LYNDA Study of Women's Health Across the Nation

5R01AG009214-12 RANCE, NAOMI Reproductive Aging and the Human Hypothalamus

5U01AG020480-03 ROBERTS, SUSAN Dietary Energy Restriction and Metabolic Aging in Humans

2U01AG012535-11A1 SANTORO, NANETTE SWAN-Study of Women's Health Across the Nation-N.J.site

5R01AG006537-18 SEALS, DOUGLAS Age, Gender, Exercise & Autonomic-Physiological Function

1R01AG022241-01A1 SEALS, DOUGLAS 

HRT, SERMs and LEG BLOOD FLOW IN 

POSTMENOPAUSAL WOMEN

1R03AG023330-01 SINGH, MEHARVAN Progesterone, GABA Receptors and Cell Survival

5R03AG022062-02 STEVENS, JUNE Obesity, diet and functional health in African-Americans

2U01AG012553-10A1 TYRRELL, KIM Study/Women/Health Across Nation III/Coordinating Center

5P60AG017231-050002 URBAN, RANDALL Androgens and nutrition in older Americans
 

76 

5K01AG019630-03 VAN PELT, RACHAEL 

ESTROGEN, INSULIN AND REGIONAL LIPOLYSIS IN 

OLDER WOMEN

5R01AG018339-05 VON MUHLEN, DENISE 

DHEA REPLACEMENT IN HEALTHY OLDER MEN 

AND WOMEN

1R01AG022073-01A1 ALLEN, SUSAN Unmet Need: An Acute/Chronic Care Link

5R01AG021203-03 ALWIN, DUANE Latent Growth Curve Models of Cognitive Aging

5T32AG000208-14 ALWIN, DUANE 

POPULATION STRUCTURE/HEALTH/BIOLOGY OVER 

THE LIFE COURSE

1Z01AG000600-16 ANDERSON, DAVID Respiratory Factors In Blood Pressure Regulation

1R43AG024676-01 BEAUCHAMP, NATASHA Multimedia Support for Caregivers of the Seriously Ill

5R01AG018760-04 BEHAN, MARY Age,Gender, Serotonin and Respiratory Control

2R01AG007977-21A2 BENGTSON, VERN A Longitudinal Study of Generations and Mental Health

5R37AG006945-18 BLAIR, STEVEN Impact of Physical Fitness and Exercise on Health

1R01AG021493-01A2 BLAUM, CAROLINE Hyperglycemia, Frailty and Disability in Older Women

5R01AG019147-04 BOOTH, SARAH Effect of Vitamin K on Age-Related Bone Loss

1K23AG021605-01A1 CARLSSON, CYNTHIA Effect of Statins on Pathobiology of Alzheimer's Disease

3T32AG000265-05S1 CARNES, MARY 

WOMEN'S HEALTH AND AGING: RESEARCH & 

LEADERSHIP TRAINING

3T32AG000265-06S1 CARNES, MARY Women's Health & Aging:Research and Leadership Training

1R01AG023802-01 COLTON, CAROL 

Immune Responsiveness, APOE/Gender in 

Neurodegeneration

1Z01AG000183-16 COSTA, PAUL Basic Research In Personality

1R03AG023301-01 DAVEY, ADAM Multilevel Analysis of Formal & Informal Care in Sweden

1R03AG022671-01A1 DUDAS, STEVEN Aging and Cancer of the Colon

1F32AG023430-01A1 DUMAS, JULIE Estrogen and Cognition In Postmenopausal Women

5R01AG018695-04 DUNN, JULIE Estrogen, Vitamin E, and Cognitive Change in Women

2R44AG019082-02 EAKER, ELAINE Testing An Interactive website for Hormone Replacement

5R01AG022987-02 ENGELHARDT, GARY Pension Wealth Calculators for Employer-Provided Plans

5R01AG005394-20 ENSRUD, KRISTINE Study of Osteoporotic Fractures

1Z01AG000513-04 EVANS, MICHELE Healthy Aging In Neighborhoods of Diversity Across Life

1Z01AG000730-09 EVANS, MICHELE DNA Damage And Repair In Breast Cancer

1P01AG023591-010003 EVANS, WILLIAM INSULIN RESISTANCE AND PROTEIN METABOLISM

5U01AG018820-04 FELSON, DAVID MULTICENTER OSTEOARTHRITIS STUDY (MOST)

2U01AG012531-11A1 FINKELSTEIN, JOEL Study of Women's Health Across the Nation - III

5K08AG020145-03 FITCHETT, GEORGE The Role of Daily Spirituality in the Disease Process

5R01AG018400-04 FLAWS, JODI Risk Factors for Hot Flashes in Mid-Life

3R37AG019905-04S1 FRIED, LINDA Pathogenesis of physical disability in Aging women

3R37AG019905-04S2 FRIED, LINDA Pathogenesis of physical disability in Aging women

5R01AG008825-12 FRIEDMAN, HOWARD PREDICTORS OF HEALTH AND LONGEVITY

2P30AG017253-069002 GARBER, ALAN 

CORE--EXTERNAL INNOVATIVE INTERNATIONAL 

NETWORK
 

77 

1R03AG024647-01 GIEBULTOWICZ, JADWIGA Longevity and reproduction in Drosophila

1R01AG025015-01 GLOWACKI, JULIE Effect of Aging & Vitamin D Status on Osteoblastogenesis

2U01AG012554-11A1 GOLD, ELLEN Study of Women's Health Across the Nation III--UC Davis

1R01AG021961-01A2 GOODPASTER, BRET Skeletal Muscle Lipid and Insulin Resistance in Aging

5P60AG017231-05 GOODWIN, JAMES 

UTMB CLAUDE PEPPER OLDER AMERICANS 

INDEPENDENCE CENTER

5R01AG015955-06 GORODESKI, GEORGE Estrogen and Aging effects on Transvaginal Transpoet

1R01AG023096-01A1 GRAVEKAMP, CLAUDIA DNA vaccines for metastatic breat cancer at old age

2U01AG012539-11A1 GREENDALE, GAIL Study of Woman's Health Across the Nation - UCLA

2P50AG005134-21 GROWDON, JOHN Massachusetts Alzheimer's Disease Research Center

5R01AG009775-12 HAUSER, ROBERT The Wisconsin Longitudinal Study: As We Age

5F32AG021374-02 HAYS, NICHOLAS Effect of diet on insulin sensitivity and energy balance

1P01AG024387-01 HELFERICH, WILLIAM 

PHYTOESTROGENS AND AGING: DOSE, TIMING & 

TISSUE

1P01AG024387-010001 HELFERICH, WILLIAM 

GENISTEIN INDUCES ENDOCRINE-RESISTANCE IN 

BREAST TUMORS

1K23AG024254-01 HESS, RACHEL Does Menopause Matter?

1R01AG024154-01 HODIS, HOWARD Biologic Response of Menopausal Women to 17B-Estradiol

5R01AG021948-02 HOYER, PATRICIA Ovary Intact Murine Model for Menopause

5R01AG011451-11 HOYER, WILLIAM AGING OF COGNITIVE MECHANISMS

5R01AG015345-07 INSOGNA, KARL Role of IL-6 in PTH-Induced Bone Resorption

5R01AG012611-10 JANOWSKY, JERI The role of sex hormones on cognition

1K01AG021457-01A2 JOSEPH, LYNDON Age, Lifestyle, Muscle Mechanisms in Insulin Resistance

5R01AG018887-04 KENNY, ANNE 

TESTOSTERONE FOR PREVENTION OF FRACTURE IN 

MEN

1K02AG023582-01 KENT-BRAUN, JANE Mechanisms of Skeletal Muscle Fatigue in Aging Adults

2R01AG012834-06A1 KIRWAN, JOHN Age, Exercise, Diet: Effects on Insulin Resistance

1R03AG023890-01 KOCH, PATRICIA Menstrual Health Disparities of Low SES African-America*

1R21AG024484-01 KRIKORIAN, ROBERT Exercise and Cognitive Aging

1R01AG023139-01A1 KUEHL-KOVARIK, MARY Functional changes in GnRH neurons with age

2P01AG004390-21A1 LIPSITZ, LEWIS HRCA/Harvard Research Nursing Home

5R03AG023108-02 MAESTAS, NICOLE The Economic Cost of Joint Retirement

5T32AG000262-07 MAGAZINER, JAY Research Training in the Epidemiology of Aging

1F32AG025640-01 MAHAY, JENNA Pathways Between Social Life and Health in Older Adults

1R01AG023522-01 MARMOT, MICHAEL Health disparities and aging in societies in transition
 

78 

1Z01AG000180-19 MCCRAE, ROBERT Stress, Coping And Personality In Aging Men And Women

5R01AG019698-04 MOHAN, SUBBURAMAN 

DETECTION OF THE SPONTANEOUS FRACTURE 

MOUSE MUTANT GENE

5R01AG013396-08 MONK, TIMOTHY PHASE SHIFT TOLERANCE IN OLDER PEOPLE

5R01AG018436-05 MROCZEK, DANIEL 

PERSONALITY AND WELL BEING TRAJECTORIES IN 

ADULTHOOD

1Z01AG000647-07 NAGARAJA, RAMAIAH Genes Assoc With Ovarian Develop /Premature Ovarian Fail

1R01AG022578-01A1 NEWTON, KATHERINE HRT Decision Making in the Post-WHI Era

1R03AG023914-01 ORDOVAS, JOSE Vitamin K: Genetics of Vascular Calcification

5R01AG011564-09 PAVALKO, ELIZA WORK AND HEALTH AMONG MID-LIFE WOMEN

5R01AG014745-07 PETITTI, DIANA Alzheimer's Disease and Estrogen Replacement

2R01AG017907-05A1 POLAN, MARY Collagenolysis and Elastolysis in Urinary Incontinence

5P50AG005136-21 RASKIND, MURRAY ALZHEIMERS DISEASE RESEARCH CENTER

1Z01AG000185-15 RESNICK, SUSAN Early Markers Of Alzheimer Disease

1R13AG023743-01 RICH, MICHAEL PRICE: Pivotal Research in Cardiology in the Elderly

1R03AG022624-01A1 ROESCH, DARREN Ovarian Senescence and Adrenal Hormone Responses

7R01AG024058-02 ROGOWSKI, JEANNETTE 

NEIGHBORHOODS AND THE HEALTH OF ELDERLY 

AMERICANS

1T32AG023475-01 ROSSETTI, LUCIANO Training in Aging Research

5R01AG019291-04 SANDBERG, KATHRYN 

HORMONAL REGULATION OF ANGIOTENSIN 

RECEPTORS

5R01AG015922-07 SANO, MARY Alzheimer's Disease Prevention Trial with Estrogens

1K08AG024816-01 SCHERZER, CLEMENS Genomic and Genetic Analysis of Parkinson's Disease

2R37AG013038-09 SEALS, DOUGLAS Human Aging, Exercise & FMD: Translational Physiology

1Z01AG007170-07 SIMONSICK, ELEANOR Treadmill Validation Of The Health ABC LDCW

5F31AG021329-02 SIMS, COLETTE Health Access/Utilization Behavior of Older Black Women

5R01AG015478-07 SINGER, DANIEL Epidemiology of Anticoagulation in Atrial Fibrillation

5P01AG022550-020004 SINGH, MEHARVAN 

MECHANISM OF PROGESTERONE-INDUCED 

NEUROPROTECTION

5R01AG017104-05 SOWERS, MARYFRAN 

FUNCTIONAL STATUS AND THE MENOPAUSAL 

TRANSITION

5R37AG021665-02 SOWERS, MARYFRAN Estrogen, Metabolism, Menopause, and Health Outcomes

5R03AG022353-02 STEVENS, JUNE Obesity in early and middle adulthood and retirement

5R01AG017919-05 SULLIVAN, EDITH 

NORMAL AGING OF BRAIN STRUCTURE AND 

FUNCTION

5P01AG023028-02 SUSSER, EZRA Early Determinants of Adult Health

1R03AG023286-01 SWINNEY, JEAN Breast Cancer in African American Women 65 and Over

5R01AG020966-02 TANAKA, HIROFUMI Resistance Training & Age-Related Arterial Stiffening
 

79 

5P30AG010124-14 TROJANOWSKI, JOHN Alzheimer's Disease Center Core

1R03AG022605-01A1 TROMMER, BARBARA Estrogen, aging, and LTP in apoE replacement mice

5P01AG011412-09 VAN CAUTER, EVE 

ALTERATIONS OF CIRCADIAN TIMING IN SLEEP AND 

AGING

5R37AG019695-03 VELDHUIS, JOHANNES 

ACTIONS OF TESTOSTERONE ON THE AGING MALE 

GH AXIS

1R37AG023188-01A1 VLASSARA, HELEN Effects of Glycoxidative Stress on Human Aging

5R01AG021487-02 WAITE, LINDA National Social Life, Health and Aging Project

5R01AG017155-05 WHITE, LON 

EPIDEMIOLOGY OF AGING AND DEMENTIA -

AUTOPSY RESEARCH

5K08AG022788-02 WILLCOX, BRADLEY Defining the Genetics of Exceptional Human Survival

5P01AG017164-05 WISE, PHYLLIS 

FEMALE REPRODUCTIVE AGING: THE ROLE OF 

ESTROGEN

5T32AG000222-13 YANKNER, BRUCE Training in the Molecular Biology of Neurodegeneration

5F31AG021880-02 YIM-CHIPLIS, PAULA MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

5U01AG021382-03 ZELINSKI-WOOTEN, MARY Ovarian Aspects of Caloric Restriction

5K01AG021999-02 ZHANG, LIANG Modulation of Osteoclastogenesis by Calmodlin Kinase II

Hormone Therapy and Women 

1R01AG024154-01 HODIS, HOWARD Biologic Response of Menopausal Women to 17B-Estradiol

5R01AG013204-08 VOYTKO, MARY LOU Cognition and Estrogen in Menopause:A Monkey Model

5K01AG020683-03 MOREAU, KERRIE HRT and Exercise Effects on Central Arterial Compliance

1R01AG022241-01A1 SEALS, DOUGLAS 

HRT, SERMs and LEG BLOOD FLOW IN 

POSTMENOPAUSAL WOMEN

1P01AG024387-010001 HELFERICH, WILLIAM 

GENISTEIN INDUCES ENDOCRINE-RESISTANCE IN 

BREAST TUMORS

2P01AG004875-210001 RIGGS, B. LAWRENCE% 

PATHOPHYSIOLOGY OF OSTEOPOROSIS IN AGING 

WOMEN

5R01AG020082-03 VITIELLO, MICHAEL PROGESTERONE AND SLEEP IN OLDER WOMEN

5R01AG014124-08 YOUNG, TERRY Menopause and Midlife Aging Effects on Sleep Disorders

1R03AG023925-01 BIMONTE-NELSON, HEATHER Progesterone, aging, and memory loss

5R01AG018339-05 VON MUHLEN, DENISE 

DHEA REPLACEMENT IN HEALTHY OLDER MEN 

AND WOMEN

5R01AG018695-04 DUNN, JULIE Estrogen, Vitamin E, and Cognitive Change in Women

1K23AG024254-01 HESS, RACHEL Does Menopause Matter?

5R01AG017057-04 NEWTON, KATHERINE 

ALTERNATIVE THERAPIES FOR MENOPAUSE: A 

RANDOMIZED TRIAL
 

80 

1R01AG022578-01A1 NEWTON, KATHERINE HRT Decision Making in the Post-WHI Era

5R01AG014745-07 PETITTI, DIANA Alzheimer's Disease and Estrogen Replacement

5R01AG015922-07 SANO, MARY Alzheimer's Disease Prevention Trial with Estrogens

5P60AG017231-050002 URBAN, RANDALL Androgens and nutrition in older Americans

5K23AG019161-03 CAPPOLA, ANNE Androgens, Myostatin, and Sarcopenia in Older Women

5R01AG017496-05 DOTY, RICHARD 

POSTMENOPAUSAL ESTROGEN INFLUENCES ON 

OLFACTION

5R01AG017170-06 ELLIOT, SHARON Estrogen Deficiency and REnal Disease in Aging Women

5R01AG019361-03 GOLD, ELLEN Sleep during the peri-menopause in a multi-ethnic cohort

5R01AG019362-03 HALL, MARTICA Sleep During the Perimenopause in a Multi-Ethnic Cohort

5R01AG018198-05 KOHRT, WENDY 

MODULATION OF VISCERAL FAT BY ESTROGENS 

AFTER MENOPAUSE

5R01AG019363-03 KRAVITZ, HOWARD Sleep During the Perimenopause in a Multi-Ethnic Cohort

2P01AG004875-210002 MELTON, L. JOSEPH III% 

RISK FACTORS FOR HIP FRACTURES AMONG THE 

ELDERLY

5R01AG012161-10 SHAPSES, SUE NUTRITIONAL REGULATION OF BONE TURNOVER

5R01AG014799-08 VELDHUIS, JOHANNES THE AGING GH AXIS IN POSTMENOPAUSAL WOMEN

5R01AG018760-04 BEHAN, MARY Age,Gender, Serotonin and Respiratory Control

2R44AG019082-02 EAKER, ELAINE Testing An Interactive website for Hormone Replacement

5R01AG012611-10 JANOWSKY, JERI The role of sex hormones on cognition

5R01AG018887-04 KENNY, ANNE 

TESTOSTERONE FOR PREVENTION OF FRACTURE IN 

MEN

1R03AG022624-01A1 ROESCH, DARREN Ovarian Senescence and Adrenal Hormone Responses

5R37AG019695-03 VELDHUIS, JOHANNES 

ACTIONS OF TESTOSTERONE ON THE AGING MALE 

GH AXIS

5R01AG017196-06 ASTHANA, SANJAY 

ALZHEIMER'S DISEASE: THERAPEUTIC POTENTIAL 

OF ESTROGEN

1R21AG023716-01 BINDER, ELLEN Testosterone Therapy After Hip Fracture in Elderly Women

1K23AG024302-01 GLEASON, CAREY Alzheimer's Disease: Potential Benefit of Isoflavones

5R01AG018798-04 HODIS, HOWARD 

ESTROGEN IN THE PREVENTION OF 

ATHEROSCLEROSIS TRIAL

5R01AG020076-03 HOLLOSZY, JOHN Is DHEA Replacement Therapy Beneficial?

5R01AG022008-02 RASGON, NATALIE Estrogen Use in Protection from Cognitive Decline

5R01AG019310-04 RYAN, ALICE Diet and Exercise: Race, Postmenopause and Metabolism

5R01AG015478-07 SINGER, DANIEL Epidemiology of Anticoagulation in Atrial Fibrillation

1R03AG022605-01A1 TROMMER, BARBARA Estrogen, aging, and LTP in apoE replacement mice

1F32AG023430-01A1 DUMAS, JULIE Estrogen and Cognition In Postmenopausal Women

5R01AG020116-02 GOLDBERG, ANDREW Race, Lipoprotein Lipase and Obesity after Menopause
 

81 

5R01AG021543-02 HARLOW, SIOBAN Staging Reproductive Aging in Five Cohort Studies

5R01AG015345-07 INSOGNA, KARL Role of IL-6 in PTH-Induced Bone Resorption

5R01AG019327-04 KNOWLTON, ANNE 

AGING, ESTROGEN, HSPS AND MYOCARDIAL 

ISCHEMIA

1R01AG023139-01A1 KUEHL-KOVARIK, MARY Functional changes in GnRH neurons with age

2U01AG012495-11A1 MCCONNELL, DANIEL Study of Women's Health Across the Nation-Endocrine Lab

2R01AG017907-05A1 POLAN, MARY Collagenolysis and Elastolysis in Urinary Incontinence

1Z01AG000191-08 RESNICK, SUSAN Neuroimaging Predictors Of Cognitive Change And Response

5R01AG019360-03 SOWERS, MARYFRAN Sleep During the Perimenopause in a Multi-Ethnic Cohort

5K01AG019630-03 VAN PELT, RACHAEL 

ESTROGEN, INSULIN AND REGIONAL LIPOLYSIS IN 

OLDER WOMEN

5-R01-AG012381-07 TAYLOR, THOMAS Decision support for preventive hormone therapy 

1-R43-AG017016-01 ZIMMERMAN, JANICE Interactive media for women considering hormone therapy 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the article, 

“Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

82 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the 

article, “Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

83 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the 

article, “Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

84 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the article, 

“Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

85 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the 

article, “Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

86 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the article, 

“Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

87 
 

Please click on this link, http://orwh.od.nih.gov/Weiss Published 2004.pdf, to access the article, 

“Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen,” published in JAMA.

88 
 

National Institute 

on Alcohol Abuse 

and Alcoholism 

(NIAAA) 

89 
Grant No. Title Principle 

Investigator 

Site Abstract 

AA011172 Tivis, Laura J. Alcohol, ERT and 

Cognition in Menopausal Women 

University of Oklahoma Hlth SciencesCtr.

Applicants Abstract: A large proportion of postmenopausal women are at least moderate consumers of alcofunctioning and psychological characteristics. Our first two aims are to determine whether drinking or use affect cognition in postmenopausal women. The third aim is to determine whether or not there are interactnature of their influence on cognitive processes. We also propose to investigate whether or not use of progfunctioning. Four groups of postmenopausal women will be recruited; teetotalers, light moderate, and modgroups, 54 will ERT, 54 will be non-users. To accomplish aim 6 the teetotalers group will contain 54 non-ERT/PRT users). Alcohol use patterns are assessed. A battery of tests that measures specific neurocognitiaccuracy, response times, and error type. Blood levels of estradiol and estrone will be measured and also upsychosocial characteristics will be administered. Psychosocial measures include demographic characterisenvironments, health history, and recent life-change events. Psychosocial subscales scores will be used as identification of risks and or benefits to cognition and psychosocial status associated with moderate drinkinknowledge and provide an increased understanding of issues surrounding women’s health care. 

AA004610 Wilsnack, Sharon C. Problem Drinking in 

Women – A 20-Year National Study

University of North Dakota 

This application proposes a national survey of 1,550 women in 2001 to increase knowledge about longitud700 women interviewed in 1981 and 1991, 350 women first interviewed in 1991, and a new same of 500 w

interviewed in 1986 and 1996). Combining the 2001 survey with the preceding surveys will produce 20-ye

longitudinal data from women over age 40 in 2001, and 10-year longitudinal data from women age 31-40 ievaluate (1) 20-year trends and age, period and cohort effects in women’s drinking behavior; (2) predictors 

drinking behavior; (3) effects on and from women’s drinking trajectories across the adult life span; (4) corrwomen and among women of childbearing age; (5) effects of question formats and interview modes on wopatterns with disordered eating behavior and with use of prescribed psychoactive drugs; and (7) cross-natio

antecedents and consequences, using data from an international collaborative project coordinated by our reinterviewers will conduct 75- minute face-to-face interviews using many questions from previous surveys 

in work and family roles, depressive symptoms, sexual and reproductive experience and relationships with trait impulsivity and additional questions about binge eating, estrogen replacement therapy, antidepressant include cross-tabular correlational and regression analyses; analysis of variance; cluster analysis (of drinkinequation modeling (for longitudinal prediction of 2001 drinking patterns); and generalized estimating equa

and survival analysis (for comparing trends and trajectories and for predicting trajectories). The 2001 survesurveys, will yield the largest, longest-term and most detailed set of longitudinal and life-historical data yet and consequences. Together with findings from the international collaborative gender and alcohol project, 

should provide a strong foundation for efforts to improve the prevention and treatment of women’s problem 

AA000219 Berman, Marlene O. Affective and 

Conative changes inAlcoholism 

Boston University

This is an application for an ADAMHA Senior Scientist Award (SSA). The SSA would permit the PI (a) texpand her research and mentoring activities concerned with gender issues in alcoholism; and (c) to gain vneuroimaging techniques. In conjunction with 2R01 AA 07112-09, investigations are planned to examine abstinent alcoholics. Secondary aims of the research are to expand studies of age-related changes and gendimportance of the research is fourfold: (1) Putative sites of alcohol-related brain damage involve separate fperceptual/cognitive aspects of emotional and intentional behaviors; (2) gender differences in alcohol-relatexploration; (3) the literature on whether emotional changes have reciprocal effects on perception and cogneven though affective and conative abnormalities have been clinically apparent in alcoholic groups, neuropchanges unrelated to emotion and intention. In the proposed experiments we will enlist the participation of age from 20 to 75 years. The experimental groups will include abstinent alcoholics with and without Korsthe alcoholics will be compared to those of age-matched nonalcoholics subjects, in order to evaluate the waalcoholism are parallel, divergent or interactive. Additionally, patients with right-frontal or bilateral frontathe necessary control comparisons for neurobehavioral changes linked directly to focal brain damage. Thecontributions to deficits of Korsakoff and non-Korsakoff alcoholics. We also will be able to evaluate hypodecline in the alcoholic and aging groups, and in women compared to men. It is expected that results of thmediated affective and conative changes in alcoholics (most notably in the Korsakoff patients), but that theuncomplicated by alcoholism. By the contrast, certain aspects of perceptual functioning will be compromialready exists. Finally, women will display different performance patterns than men. 

90
Grant No. Title Principle 

Investigator 

Site Abstract 

AA011954 Helzer, John E. Enhancing Brief 

Intervention of Primary CarePhysicians 

University of Vermont & St. Agric College

Interactive Voice Response (IVR) is a computer-based telephone technique that allows subjects to respond 

inputs brief numeric answers using the telephone touch pad. In a series of studies, we have been using the alcohol consumption over time and its relation to alcohol problems. In this study we propose to test IVR in physicians’ brief alcohol interventions with heavy and problem drinkers. Method: after brief alcohol interv

clinics, consenting patients meeting our selection criteria will be randomized to one of four study groups. Brief intervention plus daily calls by the subject to the IVR: III) Brief intervention plus daily IVR calls witvia the physician. Group IV will receive the same treatment as group III, but subjects in Group IV will rec

compliance rate. Goals: We will assess: 1) The feasibility of using IVR as an intervention in primary care the consumption reports, and 2) Whether an IVR with or without patient feedback enhances the effects of a 

objective is to develop interventions specifically designed to capitalize on the unique advantages of an IVR cost interventions for heavy and problem drinking that can be accessed remotely and are applicable in prim

AA014441 Abdel-Rahman, Abdel A Mechanisms of 

Alcohol-Estrogen HemodynamicInteraction 

East CarolinaUniversity

Alcohol elicits unique cardiovascular responses in the female population that are not only different from ththe ovarian hormones, particularly estrogen. The objective of this proposal is to elucidate the molecular mehemodynamic responses elicited by ethanol in female rats. Given the remarkable resemblance of the estrogthe manifestations associated with mild endotoxicemia, we hypothesize that the NOS-NO signaling pathwahypothesis, we propose to conduct a series of integrative, signal transduction and gene expression studies uof the vascular and/or cardiac nitric oxide synthases (NOS) mediates the estrogen-dependent hypotension arats. Since increased production of NO in the nucleus tractus solitarius (NTS) elicits hypotension, aim 2 studerived NO in the NTS caused by additive or synergistic ethanol-estrogen interaction is implicated in the hethanol in female rats. Aim 3 studies will identify the cellular mechanisms implicated in the chronic estrogof ethanol in a model of surgical menopause. The proposal adopts a well-designed experimental approach tcontrols, and pharmacological interventions to: (i) establish a causal relationship between the up-regulation vascular smooth muscle) and neurons (NTS) and the estrogen-dependent cardiovascular effects of ethanol, the actions of ethanol, estrogen and their combination on NOS-NO signaling. The proposed research, whosestrogen-dependent he

modynamic effects of ethanol, addresses in a timely manner a significant biomedica

information. 

AA005965 Pfefferbaum, Adolf CNS DefectsInteraction of Age 

and Alcoholism 

SRIInternational 

DESCRIPTION:

We propose to continue using magnetic imaging (MRI), neuropsychological (NP) and e

findings of CNS deficits associated with chronic alcoholism and aging. Our MRI studies of alcoholic man 

callosum, hippocampus, and mammillary bodies and enlargement of cortical sulci and lateral and third vendeficits particularly striking in the prefrontal cortex. Electrophysiologically, the latency of P300, a physiolmen with an exaggerated prolongation in older alcoholics; further P300 latency and indices of tissue loss aNeuropsychologically, alcoholic men show deficits in executive abilities, short-term memory, fluency and balance. Our longitudinal studies demonstrate recovery of gray matter volu

me with abstinence and further 

For the competitive renewal, we propose the following studies: Study 1: fMRI experiments of localized bra

working memory tasks. This study is designed to determine whether alcoholics show a pattern of cortical aobserved in controls, and whether underlying structural deficits influence the pattern of fMRI activation. Sinterhemispheric transfer time designed to assess the functional significance of corpus colossal thinning. Stalcoholic and control women. This study is designed to identify cross sectional patterns of sparing and los

findings in alcoholic men. Cross-sectional findings will be examined longitudinally to determine their inteaging and to assess the extent to which deficits normalize with sobriety or are exacerbated with continued dsample of older alcoholic men and women and their controls in order to extend with refined anatomical an

AA014039 Nixon, Sara Moderate Alcohol in 

Older Adults: A Preliminary Study

UniversityKentuckyLexington 

 Despite the recognition that the cohort of older adults continues to increase, that older adults remain social

and that alcohol may adversely interact with common medications and various functions, systematic researremarkably limited. It is restricted by narrow test batteries, the inclusion of largely male samples and/or the 

study was designed to address some of these limitations. Specifically, it would provide critical preliminary moderate alcohol and the effects of continued moderate drinking on neurocognitive, neurophysiological, anfunctioning and adaptation. To complete this initial work, 148 older moderate drinkers between the ages of double-blind placebo-controlled design. The re

maining 16 (8 male/8 female) will comprise a comparison g

neither expected nor administered, Because older women are a particularly understudied group, every attemfemale drinkers. Data collected from this study will provide critical information regarding the effects of acu

of domains and will also provide comparison data with younger substance abusing and community control 

ensuring appropriate protocol development, training, pilot work and initial data collection, would provide taging focus in our on-going research program. 

91
Grant No. Title Principle 

Investigator 

Site Abstract 

AA000115 Hibbeln, Joseph R. Essential Fatty Acids 

In Psychiatric Disorders 

National Institute On Alcohol Abuse And Alcoholism LMBB 

This project examines whether inadequate dietary intakes of omega-3 essential fatty acids increases the risk specifically depression, aggression and suicide. Randomized placebo controlled clinical interventional trial

aggressive alcoholics, wo

men with depression during pregnancy and suicide attempters. These studies hav

the prevalence rates of several psychiatric disorders when comparing populations with high or low measure 3 fatty acid tissue concentrations in epidemiological studies. Nutritional inadequacies during early developcontribute to an increased predisposition toward psychiatric disorders in adulthood. Developmental outcomof aggressive alcoholics, the key questions are to assess if treatment with 2.8 g/d of omega-3 fatty acids wimeasures of serotonergic function 3) improve cardiovascular measures thought to be associated with depreenrolled 19 subjects with a 100% tracking of data. Preliminary results are not available until completion unfor Fall 2005. In collaboration with Garth Bissett, Ph.D. we determined that low plasma DHA levels predicCSF of perpetrators of domestic violence. This finding, now in press, may lead to down regulation of the Hcurrently being tested in a placebo-controlled, intervention trial of aggressive alcoholics. In collaboration wplasma levels of DHA and AA predicted relapse a

mong cocaine and alcohol dependent subjects over the co

to determine if supplementation with omega-3 fatty acids will actually reduce relapse in a randomized cont

essential fatty acids during pregnancy when their dietary intake is inadequate. Dietary deficiencies may incPreliminary data is available from an open trial of omega-3 fatty acids a

mong women with depression duri

with Marlene Freeman, MD at the University of Arizona. Depressive symptoms were reduced an average osignificant as they offer a treatment for depression during pregnancy that is not only non-toxic, but has addThese findings are being followed up with a randomized, controlled trial. The results of these interventionastudy of the dietary intake of omega-3 fatty acids during pregnancy among nearly 14,000 wo

men enrolled 

(ALSPAC). In clear dose-response relationships, deficient intakes were associated with nearly a doubling ogestation (p<1.4 X 10 -17) and 18 weeks gestation and at both 8 weeks and 8 months postpartum. Findings confounding factors. Deficient intake of omega-3 essential fatty acids during early development may also hIn collaboration with the ALSPAC study, we found that deficient intake of omega-3 fatty acids during pregbehaviiioral disorders among children at both 3.5 and 7 years of age. A dose response relationship predicte

fighting, lying, stealing, disobedience, which are well recognized risk factors for future sociopathic and criM.D and Jean Golding, Ph.D. in designing a study to prospectively capture initial drinking behavior of theevaluated to determine if inadequate intake during pregnancy or early childhood is a risk factor for future sprevention studies can be planned. A significant finding was that compliance with the FDA and EPA meth

consumption during pregnancy inadvertently creates harm in the specific developmental domains in which 

was examined by either compliance or exceeding intake described by the advisory. These finding are curreanalysis we found higher rates of homicide mortality were correlated to lower rates of seafood consumptioobservation that the omega-6 fatty acids from seed oils compete for space in the tissues with omega-3 fatty to 2000, the increasing rates of homicide mortality were closely correlated with increasing availability ome

Kingdom, Australia and Canada. This association is also consistent with observational and interventional dinvestigators. 2) In collaboration with Dr. Carlos Iribarren, we examined the dietary intake of omega-3 fattin the CARDIA trial, lower intake of DHA and other omega-3 fatty acids predicted a doubling of the risk oan interventional trial conducted in collaboration with Dr. Muldoon at the University of Pittsburgh, subject(a cholesterol lowering drug) or a placebo for 8 weeks. We quantified changes in mood, cognition and plasSimvistatin lowered total fatty acid concentrations, but spared DHA and AA. The relationship between the decrements in mood and cognition are still under examination. 

AA014211 Colrain,, Ian Alcoholism, Sleep 

and the Brain SRI

International 

Acute and chronic alcohol consumption causes sleep disturbances, which may never resolve and may be a deficits also become more pronounced with advancing age. The most consistently reported finding of alteroccurring slow wave sleep (SWS), defined by the presence of delta EEG activity. Further, alcoholics with r

relapse. External stimulation during sleep can elicit K-complexes, which when averaged produce a large Ndelta activity. Given the potential value of sleep markers in predicting relapse, it would be advantageous to 

under experimenter control rather than one that relies on the traditional observation of spontaneous sleep pevoked N550 component amplitudes are smaller and K-complexes are produced on a smaller number of triindicates that alcoholics have even smaller N550 than would be expected for their age. A candidate genera

matter, which is especially reduced in older alcoholics. Sex differences in brain structure and electrophysio

and objective study of them may further contribute to our understanding of relevant mechanisms of alcohofollowing hypotheses: Hypothesis 1: Recently detoxified, chronic alcoholics will have smaller N550 amplilevels and delta EEG power compared to sex- and age-matched controls. Hypothesis 2: Low evoked K-comlevels and delta EEG power will be associated with small prefrontal gray matter volume. Hypothesis 3: Alc

alcoholic wo

men. Hypothesis 4: S

mall amplitude, production rate and power of sleep electrophysiological 

relapse. 

92
 

National Institute 

of Allergy and 

Infectious Diseases 

(NIAID) 

93 
 

National Institute of Allergy and Infectious Diseases 

Menopause Related Research 

The NIAID Division of Allergy, Immunology, and Transplantation has an active interest in the 

sex based differences in the immune response, including the effects of sex hormones on 

immunologic function. Autoimmune diseases, which result from a disordered attack of the 

immune system on the body’s own tissues, affect an estimated 5 to 8 percent of the U.S. 

population and disproportionately afflict women. Ongoing relevant studies include: 

1. Sex hormone regulation of innate immunity, P01-AI-051877, PI: Charles Wira, 

Dartmouth Medical School 

The overall objective of this Program Project is to define the role of sex hormones 

(androgens, estrogens and progestins) in regulating the innate immune system as it 

functions systemically and at mucosal surfaces. Mechanisms whereby sex hormones 

influence phenotype, innate function, and communication between the innate and 

adaptive immune systems will be defined. Peripheral blood cells from men and women, 

cell lines, and immune cells and tissues from the female reproductive tract will be utilized 

to define the role of sex hormone and pathogenic challenge at the cellular and molecular 

level. The hypothesis is that innate immunity (epithelial cells, neutrophils, macrophages 

and NK cells) is under male and female sex hormone control and that, in addition to 

conferring protection, each of these cells is capable of initiating an adaptive immune 

response. 

2. Protein targets of ovarian and oocyte autoantibodies, R01-AI-055060, PI: Judith 

Luborsky, Rush Medical College 

Ovarian autoimmunity may affect 1-2 million women in the US. In order to identify 

women with ovarian autoimmunity, prototype immunoassays were developed to detect 

ovary specific autoantibodies. The results were used to develop phenotypic information 

on the association of ovarian autoimmunity with premature menopause (premature 

ovarian failure) and unexplained infertility. 

Further human research and clinical use depends on identification of the relevant protein 

antigens. The objective of the proposed study is to identify major autoantigens relevant to 

the phenotypes associated with ovarian autoimmunity. Previous studies showed that 

ovarian antibodies are associated with a low likelihood of pregnancy after infertility 

treatment. The proposed study is expected to improve the precision with which ovarian 

autoimmunity is detected. This will permit studies of disease 

pathogenesis, health risks associated with ovarian autoimmunity, genetic factors 

associated with disease susceptibility, and improve clinical diagnosis. It will also 

94 
 

95 

contribute to a better understanding of an autoimmune disease that affects women's 

health. 

3. Molecular consequences of estrogen-induced interferon, R01 AI051880, PI: Ansar 

Ahmed, Virginia Polytechnic Institute and State University 

Sex hormones, such as estrogens, are believed to play a major role in gender-based 

differential immune competence and autoimmunity. One mechanism by which estrogens 

may influence the immune system is by regulating cytokine levels. This grant is aimed at 

mechanistically studying how estrogen alters the production of interferon and the 

molecular consequences of increased interferon Estrogen-induced interferon is 

significant, since interferon is a "master" cytokine with physiological effects on nearly all 

cells of the immune system. This project will examine the molecular basis for production 

and action of estrogen-induced interferon. 

4. Sex-based differences in the immune response, R01 AI 051767, PI: Betty Diamond, 

Yeshiva University 

It has long been hypothesized that sex hormones play a role in immune regulation and 

specifically in systemic lupus erythematosus. Estrogens can alter the threshold for 

negative selection of naive autoreactive B cells and may thus influence the development 

of autoimmune diseases. This project will examine how estrogen leads to an increase 

specifically in cells of the marginal zone B cell subset. In addition, experiments will be 

conducted to investigate the differences in B cell responsiveness to estrogen in different 

mouse strains to understand what underlies an estrogen-mediated breakdown in humoral 

self- tolerance. 

5. Sex-based differences in regulatory T cell responses, R21 AI 051870, PI: Michele 

Kosiewicz, University of Louisville 

 Many autoimmune diseases are much more prevalent in women compared to men, 

including multiple sclerosis, arthritis and systemic lupus erythematosus. Although the 

reason for this difference is not currently known, the sex hormones are likely to play a 

significant role. A recently described population of naturally occurring regulatory T cells, 

CD4+CD25+, is responsible for controlling autoimmune disease in mice. Elimination of 

this population in mice results in severe multi-organ autoimmune diseases. This project 

will test the hypothesis that sex steroids mediate the gender differences in CD4+ CD25+ 

regulatory T cells, and through this mechanism may influence the differential expression 

of autoimmune disease in females versus males. The results of these studies will provide 

important information that can lead to the development of novel therapies for the 

prevention and treatment of autoimmune disease. 

6. Sex hormone regulation of the mucosal immune system, 5 R37 AI013541-23, PI: 

Charles Wira, Dartmouth 

The broad objectives of the research proposed in this application are to understand at the 

cellular and molecular levels, the physiological actions of sex hormones on the mucosal 

immune system. These actions account for changes in humoral and cellular immunity and 
 

96 

have clinical applications in the treatment of venereal diseases, autoimmune diseases, 

malignancy, infertility and fertility control. Studies will be undertaken to: (1) examine the 

regulation by sex hormones and antigens of immune cells in the female reproductive 

tract; (2) elucidate the role of selected cytokines in the response of the genital tract to 

antigens and identify the way in which they interact with sex hormones to influence 

mucosal immunity; (3) identify the mechanism(s) responsible for estradiol-regulated 

movement of IgA and IgG; and (4) study the role of sex hormones antigens and cytokines 

in regulating secretory component (SC) and IgA gene expression. 

Current Publications 

1. Shen L, Fahey JV, Hussey SB, Asin SN, Wira CR, Fanger MW. Synergy between IL-8 

and GM-CSF in reproductive tract epithelial cell secretions promotes enhanced 

neutrophil chemotaxis. Cell Immunol. 2004 Jul; 230(1):23-32. 

2. Schaefer TM, Desouza K, Fahey JV, Beagley KW, Wira CR. Toll-like receptor (TLR) 

expression and TLR-mediated cytokine/chemokine production by human uterine 

epithelial cells. Immunology. 2004 Jul; 112(3):428-36. 

3. Eriksson M, Meadows SK, Wira CR, Sentman CL. Unique phenotype of human uterine 

NK cells and their regulation by endogenous TGF-beta. 

J Leukoc Biol. 2004 Sep; 76(3):667-75. Epub 2004 Jun 03 

4. Crane-Godreau MA, Wira CR.Effect of Escherichia coli and Lactobacillus rhamnosus on 

macrophage inflammatory protein 3 alpha, tumor necrosis factor alpha, and transforming 

growth factor beta release by polarized rat uterine epithelial cells in culture. Infect 

Immun. 2004 Apr; 72(4):1866-73. 

5. Peeva E, Venkatesh J, Michael D, Diamond B. Prolactin as a modulator of B cell 

function: implications for SLE. Biomed Pharmacother. 2004 Jun; 58(5):310-9. 

 
 

National Institute 

of Arthritis and 

Musculoskeletal 

and Skin Diseases 

(NIAMS) 

97 
 

98 

National Institute of Arthritis and Musculoskeletal and Skin Diseases 

Menopause Research FY 2003-2004 

Overview 

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) supports 

research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin 

diseases, the training of basic and clinical scientists to carry out this research, and the 

dissemination of information on research progress in these diseases. Many of the diseases in our 

research portfolio disproportionately affect women, particularly menopause-related conditions 

such as osteoporosis. The NIAMS is committed to uncovering the scientific bases of these 

disparities and to devising effective strategies to treat or prevent them through a broad portfolio 

of menopause- and hormone-related research. 

 

Osteoporosis is a skeletal disorder marked by reduced bone strength that predisposes a person to 

an increased risk of fractures. Osteoporosis poses a major public health challenge for both 

women and men. Women, in particular, have and increased risk of developing osteoporosis 

because of accelerated bone loss at menopause. NIAMS supports a broad portfolio of grants 

focused on our understanding of the relationship between menopause and osteoporosis. Specific 

examples include research examining the impact of exercise on bone mineral density (BMD). 

Recent studies have shown that aerobic, weight-bearing and resistance exercise improves BMD 

in postmenopausal women whether or not they use hormone therapy. Other NIAMS-supported 

researchers are exploring the cellular and molecular basis of parathyroid hormone (PTH) on 

bone. PTH is a medication used to treat osteoporosis and has been shown to stimulate new bone 

formation. NIAMS-supported researchers are also exploring new areas of research including the 

effects of soy on bone in non-osteoporotic early postmenopausal women. Additional research is 

focusing on the signaling pathways involved in bone formation and bone loss. An improved 

understanding of these pathways could furnish new principles for the development of measures 

to improve bone quality and prevent menopause-associated osteoporosis. 

FY 2003-2004 Menopause Research Advances 

Exercise Builds Bone Mass in Postmenopausal Women Whether or Not They Use Hormone 

Therapy 

NIAMS-supported investigators conducted a randomized clinical trial in 320 postmenopausal 

women between the ages of 45 and 65 to test the effect of a specific exercise regimen on bone 

mineral density. The women who were randomized to the exercise regimen – a combination of 

weight-bearing and resistance exercises – showed significant improvement (1 to 2 percent) in 

BMD after one year at the hip and spine, two important sites of fractures that may result from the 

osteoporosis. Notably, this benefit was found in both women taking postmenopausal hormone 

therapy and those who did not, although the women taking hormones had a somewhat greater 

response to exercise. 

The study shows that specific strength training and resistance exercises can retard and even 

reverse bone loss in healthy postmenopausal women, and that estrogen replacement is not 

necessary to gain the benefit of the exercise. All women received calcium supplements, and 

adequate calcium may be a factor in optimizing the effect of exercise on bone in postmenopausal 

women. These findings may provide reassurance for women who no longer take hormone 

replacement therapy because of the recent Women's Health Initiative findings. 

Inhibiting Enzyme Increases Bone Density 
 

99 

NIAMS-supported researchers have used a combination of mouse breeding and genetic 

technology to identify a gene that strongly influences peak bone mass in mice. The gene, which 

is present in humans as well as mice, was not previously known to be involved in bone biology, 

and hence represents a promising new target for development of drugs that could prevent or 

reverse the bone loss that leads to osteoporosis. Peak bone mass, acquired early in life, is 

thought to be an important factor in the risk for osteoporosis in humans. 

Researchers studied the offspring of a mating between mouse strains with markedly different 

peak bone mass, and identified a particular region of one chromosome which influences peak 

bone mass. Subsequently, their studies of the genes located within this region showed that the 

Alox15 gene, which produces an enzyme called 12/15-lipoxygenase (12/15-LO), was much more 

active in the low-bone mass strain than in the high-bone mass strain. Follow-up experiments 

confirmed the effects of 12/15-LO on bone mass in mice. 

In a further phase of the study, the researchers investigated the effect of pharmacological 

inhibitors of the 12/15-LO enzyme. These drugs had already been developed to inhibit 12/15-

LO in other conditions, such as atherosclerosis (clogged arteries), cancer, and asthma, in which 

this enzyme is also thought to play a role. The use of these drugs resulted in an increase in BMD 

throughout the body in mice that were estrogen-deficient after removal of the ovaries. Reduction 

in estrogen production with menopause is the major cause of loss of BMD during later life. 

While further animal and human investigation into the role of 12/15-LO in the development of 

osteoporosis is needed, the results of this study suggest that inhibition of 12/15-LO may play a 

role in osteoporosis treatment and prevention. 

NIAMS-Supported Menopause Grants FY 2003-2004

Grant 

Number 

PI Name Institution Project Title 

AR042540 BUYON, JILL P. HOSPITAL FOR JOINT 

DISEASES ORTHO INST 

SAFETY OF ESTROGEN IN 

LUPUS 

ERYTHEMATOSUSNAT'L ASSESS' 

AR049701 MAJUMDAR, 

SHARMILA 

UNIVERSITY OF 

CALIFORNIA, SAN 

FRANCISCO 

VERTEBRAL FRACTURE: 

TRABECULAR BONE 

STRUCTURE 

ASSESSMENT 

AR046859 PREVRHAL, SVEN UNIVERSITY OF 

CALIFORNIA SAN 

FRANCISCO 

MEASUREMENT OF 

THICKNESS/DENSITY OF 

THE PROXIMAL FEMUR 

AR050618 SNYDER PETER J UNIVERSITY OF 

PENNSYLVANIA 

WILL TESTOSTERONE 

/GROWTH HORMONE 

IMPROVE BONE 

STRUCTURE 
 

100 

AR048205 VOKES TAMARA UNIVERSITY OF CHICAGO CLINICAL UTILITY OF 

TEXTURE ANALYSIS IN 

OSTEOPOROSIS 

AR044855 KRONENBERG, 

HENRY M 

MASSACHUSETTS GENERAL 

HOSPITAL 

SPECIALIZED CENTER 

FOR RESEARCH IN 

OSTEOPOROSIS 

AR041325 BOSKEY, ADELE HOSPITAL FOR SPECIAL 

SURGERY 

FT-IR MICROSCOPY OF 

MINERAL STRUCTURE IN

OSTEOPOROSIS 

AR042906 BROOKS, GEORGE UNIVERSITY OF 

CALIFORNIA BERKELEY 

EXERCISE SUBSTRATE 

UTILIZATION: THE 

CROSSOVER CONCEPT 

AR050662 CHANG, WENHAN NORTHERN CALIFORNIA 

INSTITUTE RES & EDUC 

RESOLUTION OF STAGESPECIFIC GROWTH 

PLATE CHONDROCYTES 

AR049633 GOLTRY, KRISTIN L AASTROM BIOSCIENCES, 

INC. 

CLINICAL-SCALE 

PRODUCTION OF 

OSTEOPROGENITOR 

CELLS 

AR050352 KINDLE, LIBBY A WASHINGTON UNIVERSITY RECRUITMENT OF 

OSTEOCLASTS FROM 

BONE 

MICROVASCULATURE 

AR050001 LI, YEFU HARVARD UNIVERSITY 

(MEDICAL SCHOOL) 

GENETIC REGULATION 

OF SKELETOGENESIS 

AR049341 LICHTLER 

ALEXANDER 

UNIVERSITY OF 

CONNECTICUT SCH OF 

MED/DNT 

DLX GENE REGULATION 

OF OSTEOBLAST 

DIFFERENTIATION 

AR046032 NAFTOLIN, 

FREDERICK 

YALE UNIVERSITY AROMATASE INHIBITOR 

METHYL TESTOSTERONE 

AND TESTOSTERONE 

INDUCED BONE SPARING

AR050201 PENG, HAIRONG CHILDREN'S HOSP 

PITTSBURGH/UPMC HLTH 

SYS 

IMPROVING BONE 

HEALING BY MYOFIBER 

DEDIFFERENTIATION 
 

101 

AR048833 TURNER, RUSSELL T MAYO CLINIC COLL OF 

MEDICINE, ROCHESTER 

ETIOLOGY AND 

TREATMENT OF 

PARATHYROID BONE 

DISEASE 

AR092237 RECKER, ROBERT M. CREIGHTON UNIVERSITY HORMONE 

REPLACEMENT 

THERAPY WITH 

ALENDRONATE IN POST 

MEN 

AR046922 ALEKEL, LEE D IOWA STATE UNIVERSITY 

OF SCIENCE & TECH. 

BONE RESPONSE TO SOY 

ISOFLAVONES IN 

WOMEN 

AR044655 BECK, THOMAS J. JOHNS HOPKINS 

UNIVERSITY 

STRUCTURAL ANALYSIS 

OF DEXA SCANS: 

OSTEOPOROSIS STUDIES

AR051702 BHATTACHARYA 

AMIT 

UNIVERSITY OF CINCINNATI A NOVEL POSTMENOPAUSAL 

OSTEOPOROSIS 

SCREENING TOOL 

AR051483 BROWN SUE A UNIVERSITY OF NORTH 

CAROLINA CHAPEL HILL 

BONE ACCRUAL AND 

HORMONES IN 

RESPONSE TO 

LACTATION 

AR50496 DENG HONG-WEN W CREIGHTON UNIVERSITY ROBUST AND POWERFUL 

TEST OF CANDIDATE 

GENES TO BONE MASS 

AR48826 FRAENKEL LIANA YALE UNIVERSITY ELICITING PATIENT 

TREATMENT 

PREFERENCES FOR 

OSTEOPOROSIS 

AR035584 HOCHBERG, MARC C UNIVERSITY OF MARYLAND 

BALT PROF SCHOOL 

OSTEOPOROTIC 

FRACTURES 

AR027065 KHOSLA, SUNDEEP MAYO CLINIC ROCHESTER EPIDEMIOLOGY OF AGE 

RELATED BONE LOSS 

AND FRACTURES 

AR041398 KIEL, DOUGLAS P. HEBREW REHABILITATION 

CENTER FOR AGED 

RISK FACTORS FOR 

AGED RELATED BONE 

LOSS 
 

102 

AR048841 LANE, NANCY UNIVERSITY OF 

CALIFORNIA SAN 

FRANCISCO 

MIDCAREER 

INVESTIGATOR AWARD 

PATIENT-ORIENTED 

RESEARCH 

AR50298 SIBONGA JEAN D MBC RESEARCH, INC. PREVENTION OF 

OSTEOPOROSIS WITH 

NOVEL 

BISPHOSPHONATES 

AR051564 WREN TISHYA AL CHILDREN'S HOSPITAL LOS 

ANGELES 

MECHANICAL 

INTERVENTION IN 

CHILDREN WITH 

CEREBRAL PALSY 

AR051124 ZMUDA JOSEPH M UNIVERSITY OF 

PITTSBURGH AT 

PITTSBURGH 

BONE STRENGTH 

PHENOTYPES IN MEN: 

GENES AND 

ENVIRONMENT 

AR050383 ARDLIE, KRISTIN G GENOMICS 

COLLABORATIVE, INC. 

OSTEOPOROSIS 

CANDIDATE GENES: IN 

SILICO AIDED 

DISCOVERY 

AR047869 BLUM, MIRIAM TUFTS UNIVERSITY BOSTON ROLE OF ADIPOSE 

TISSUE IN VITAMIN D 

METABOLISM 

AR035582 CAULEY, JANE A UNIVERSITY OF 

PITTSBURGH AT 

PITTSBURGH 

STUDY OF 

OSTEOPOROTIC 

FRACTURES 

AR049411 CHEN, ZHAO UNIVERSITY OF ARIZONA LONGITUDINAL 

CHANGES IN HIP 

GEOMETRY AND 

SKELETAL MUSCLE 

AR048919 CUMMINGS, STEVEN 

R 

CALIFORNIA PACIFIC MED 

CTR-PACIFIC CAMP 

WHI SEX HORMONE & 

GENETIC RISK FACTORS 

FOR HIP FRACTURE 

AR045614 ENSRUD, KRISTINE E UNIVERSITY OF MINNESOTA 

TWIN CITIES 

OSTEOPOROTIC 

FRACTURES IN MEN 

AR002161 GREEN, REBECCA P WASHINGTON UNIVERSITY PREVENTION OF 

STERIOD INDUCED 

OSTEOPOROSIS IN 

CHILDREN 

AR048846 HEANEY, ROBERT P CREIGHTON UNIVERSITY BONE-SPARING BY CA 

SALTS WITH & WITHOUT 

EXTRA PHOSPHORUS 
 

103 

 AR035583 HILLIER, TERESA A KAISER FOUNDATION 

RESEARCH INSTITUTE 

STUDY OF 

OSTEOPOROTIC 

FRACTURES 

AR035584 HOCHBERG, MARC C. UNIVERSITY OF MARYLAND 

BALT PROF SCHOOL 

STUDY OF 

OSTEOPOROTIC 

FRACTURES 

AR050066 KARASIK, DAVID HEBREW REHABILITATION 

CENTER FOR AGED 

GENETICS OF BONE 

STRUCTURAL 

GEOMETRY: 

FRAMINGHAM COHORTS

AR049439 LAU, EDITH MC CHINESE UNIVERSITY OF 

HONG KONG 

OSTEOPOROTIC 

FRACTURES IN CHINESE 

MEN: MROS HONG KONG

AR048932 LEVIS, SILVINA UNIVERSITY OF MIAMIMEDICAL BONE SPARING EFFECTS 

OF SOY 

PHYTOESTROGENS IN 

MENOPAUSE 

AR045632 LEWIS, CORA 

ELIZABETH 

UNIVERSITY OF ALABAMA 

AT BIRMINGHAM 

OSTEOPOROTIC 

FRACTURES IN MEN 

(MR.OS) 

AR047932 MILLIKEN, LAURA A UNIVERSITY OF 

MASSACHUSETTS BOSTON 

FACTORS AFFECTING 

THE BONE RESPONSE 

AND NON-RESPONSE 

AR050450 ORCHARD, PAUL J UNIVERSITY OF MINNESOTA 

TWIN CITIES 

FIRST INTERNATIONAL 

SYMPOSIUM ON 

OSTEOPETROSIS: 

AR045647 ORWOLL, ERIC S. OREGON HEALTH & 

SCIENCE UNIVERSITY 

OSTEOPOROTIC 

FRACTURES IN MEN 

(MR.OS) 

AG022326 PEREIRA-SMITH, 

OLIVIA M 

GERONTOLOGICAL SOCIETY 

OF AMERICA 

CONFERENCE--BIOLOGY 

OF AGING 

AR048616 SOLOMON, DANIEL H BRIGHAM AND WOMEN'S 

HOSPITAL 

RANDOMIZED 

CONTROLLED TESTING 

OF OSTEOPOROSIS 

EDUCATION 

 AR047852 SPECKER, BONNY L SOUTH DAKOTA STATE 

UNIVERSITY 

BONE DENSITY AND 

LATER BONE LOSS IN 

RURAL POPULATIONS 

AR045583 STEFANICK, MARCIA 

L 

STANFORD UNIVERSITY OSTEOPOROSIS IN MEN 
 

104 

AR049401 VILLAREAL, REINA C BARNES-JEWISH HOSPITAL CYP GENE 

POLYMORPHISM AND 

ESTROGEN STATUS IN 

THE ELDERLY 

AR049747 ZMUDA, JOSEPH M UNIVERSITY OF 

PITTSBURGH AT 

PITTSBURGH 

EPIDEMIOLOGY OF BONE

LOSS IN AFRICAN MEN 

AR050107 ZMUDA, JOSEPH M UNIVERSITY OF 

PITTSBURGH AT 

PITTSBURGH 

DETERMINANTS OF 

BONE STRENGTH IN 

AFRO-CARIBBEAN 

FAMILIES 
 

National Institute 

of Child Health 

and Human 

Development 

(NICHD) 

105 
 

THE NATIONAL INSTITUTE OF CHILD HEALTH AND 

HUMAN DEVELOPMENT (NICHD) 

Research Related to The Menopausal Transition 

(Report of the NIH Office of Research on Women’s Health and the 

Coordinating Committee on Research on Women’s Health) 

The NICHD has a unique role to play in women’s health research. Although the Institute’s 

mission is to ensure that babies are born wanted, timely, and healthy and that they develop to 

their full physical, emotional, and cognitive potentials, NICHD-sponsored research spans human 

growth and development. Given its mission, the NICHD portfolio includes a broad array of 

behavioral, basic, and clinical research on women’s reproductive health, including studies related 

to menopause, to conditions that may be associated with physiological changes that lead to or 

occur in menopause, and to issues that may be related to hormone replacement therapy. 

Highlighted here are just some of the Institute’s newest research projects related to menopause. 

NICHD-supported researchers are examining some of the behavioral aspects related to 

menopause. For instance, to improve communication between healthcare providers and diverse 

groups of women about menopause and treatment recommendations, researchers are 

interviewing Latin, African-American, Japanese-American, and white women about their own 

understandings of menopause. The findings will allow researchers to develop culturallysensitive interventions that may help healthcare providers to better communicate medical 

information about menopause to their patients. 

In addition to behavioral research, the Institute supports basic research related to menopause. 

For instance, researchers are examining how menopause changes vaginal connective tissue and 

weak tissues that can result in pelvic organ prolapse. In the same study, the researchers will also 

examine whether hormone therapy in postmenopausal women improves the structural 

deficiencies in the vaginal connective tissue compared to postmenopausal women who are not 

taking a hormone therapy. 

 

NICHD-supported researchers are also conducting a pilot study to test whether the drug, 

gabapentin, could be an effective treatment for hot flashes. The preliminary findings from this 

study may enable the researchers to design a full-scale randomized trial to test the effectiveness 

of this potential new drug. The findings from this and from all of the studies highlighted here 

may help researchers to develop methods to better treat and prevent menopausal symptoms and 

disorders related to aging, improving the quality of life for women. 

106 
 

Project Number Title Investigator's Name Institution 

K08HD001463 

THE ROLE OF ESTROGEN IN 

BONE METABOLISM OZ, ORHAN K 

UNIVERSITY OF TEXAS SW MED 

CTR/DALLAS 

K23HD044729 

Bridging Menopause: 

Experiences/Clinical Encounters 

HILL-SAKURAI, 

LAURA E 

UNIVERSITY OF CALIFORNIA SAN

FRANCISCO

K24HD001290 

NEUROENDOCRINE 

CONTROL OF 

REPRODUCTION IN THE 

FEMALE HALL, JANET E 

MASSACHUSETTS GENERAL 

HOSPITAL 

R01HD038673 

MODEL FOR PELVIC FLOOR 

DISORDERS CLARK, AMANDA L

OREGON HEALTH & SCIENCE 

UNIVERSITY 

R01HD038679 

MECHANISMS OF 

INCONTINENCE 

FOLLOWING VAGINAL

DISTENSION 

DAMASER, 

MARGOT S. LOYOLA UNIVERSITY CHICAGO 

R01HD041131 

Natural History of POP-- A 

Prospective Cohort Study

NYGAARD, INGRID

E NIVERSITY OF IOWA 

R01HD043355 

Estrogen Receptor Variance and 

CHD Risk in HERS 

HERRINGTON, 

DAVID M 

WAKE FOREST UNIVERSITY HEALTH 

SCIENCES 

R01HD045590 

IMPACT OF MENOPAUSE ON 

VAGINAL CONNECTIVE 

TISSUE SUPPORT MOALLI, PAMELA A

MAGEE-WOMEN'S HEALTH 

CORPORATION 

R03HD042609 

Gabapentin vs Estrogen for the 

Treatment of Hot Flushes REDDY, SIREESHA UNIVERSITY OF ROCHESTER 

U54HD041748 

TESTOSTERONE RESPONSE 

IN SURGICALLY 

MENOPAUSAL WOMEN 

DHASIN, 

SHALENDER 

CHARLES R. DREW UNIVERSITY OF 

MED & SCI 

Z01HD000628

REGULATION OF GROWTH 

AND REPRODUCTION

BONDY, CAROLYN 

A NICHD

Z01HD000633

OVARIAN 

FOLLICULOGENESIS 

NELSON, 

LAWRENCE M NICHD 

NICHD Menopause-related Research: 2004 

107 
 

108 
 

National Institute 

on Deafness and 

Other Communication Disorders 

(NIDCD) 

109 
 

110 

National Institute on Deafness & Other Communication 

Disorders 

Menopause Related Grants 

Title Grant Number Principal 

Investigator 

Institutition 

GENES INVOLVED 

IN THE 

DEVELOPMENT OF 

VESTIBULAR 

OTOCONIA 

R01DC02236-09 ORNITZ, DAVID M WASHINGTON 

UNIVERSITY, ST. 

LOUIS 

The vestibular organs of the inner ear include the otolith organs, used for detecting gravity and 

linear acceleration, which are important for postural and locomotor control. These organs are 

small pouches containing a matrix of dense calcified crystals called otoconia, imbedded in a 

proteinaceous matrix. Functional deficits in the vestibular system can lead to sensations of 

dizziness and vertigo, postural instability, and falling or vehicular accidents that can have serious 

medical consequences. Problems with balance are a leading cause of death and injury in elderly 

populations. 

The project headed by Dr. Ornitz investigates the mechanisms by which the otoconia are formed, 

using mutant mouse models to identify genes that are expressed in the mammalian vestibular 

system during the development of the otoconia. Progress thus far has identified mutations in a 

new gene named otopetrin, showing its apparent requirement for correct otoconial development, 

and compared two proteins called Oc90 and Oc22 that are important for forming the protein 

matrix. These studies will provide molecular and biochemical tools to clarify the formation and 

turnover of otoconia. Human otoconia undergo changes involved with aging, compounded by 

potential problems related to changes in calcium metabolism, such as those related to bone 

degeneration in osteoporosis. This combination is particularly important in post-menopausal 

women, if aging vestibular dysfunction results in increased susceptibility for falls, with the 

potential for bone fracture injuries. Having a genetic tool for otoconial development gives some 

promise for restoring losses of otoconial structure and function. 

 
 

111 

National Institute 

of Dental and 

Craniofacial Research 

(NIDCR) 
 

112 

National Institute of Dental and Craniofacial Research 

The mission of the National Institute of Dental and Craniofacial Research (NIDCR) is to 

improve oral dental and craniofacial health through research, research training and the 

dissemination of health information. The Institute supports research in areas such as acquired 

and congenital conditions, infectious diseases (periodontal diseases and dental caries), oral 

cancers, oral manifestations of HIV infections, chronic and disabling disorders such as bone and 

joint diseases, and neurological and neurosensory disorders with emphasis on chronic pain. 

Research advances affecting women can be found within a number of these broad research 

categories. 

Menopause Related Research 

Role of Serotonin in Osteoclast Differentiation: The goal of this project is to identify and 

characterize the interactions between the neuroendocrine and skeletal systems. Recently, 

investigators reported that serotonin, a well-established neurotransmitter, regulates the activities 

of osteoclasts, which are bone-resorbing cells. Deregulation of the serotoninergic system leads 

to depressive disorders and other psychological disturbances. In the U.S., twice as many women 

as men are affected by a depressive disorder each year. This study suggests that serotoninergic 

disorders may be associated with changes in bone mass. This study also indicates that 

commonly prescribed anti-depressants that target the serotoninergic system, e.g. Prozac, may 

affect bone health and could be exacerbated in perimenopausal women. 

Low-Dose Doxycycline Effects On Osteopenic Bone Loss: The objective of this study is to 

assess the clinical efficacy of low-dose doxycycline therapy in reducing bone loss caused by 

periodontitis and estrogen deficiency in postmenopausal women. The study is a 5-year, doubleblinded randomized controlled trial using a placebo. Clinical measurements of periodontal 

disease and oral bone loss include probing depths, gingival attachment level and crevicular fluid. 

In addition, the systemic effect of low-dose doxycycline will be evaluated by dual-energy x-ray 

absorptiometry of the lumbar spine and femoral neck, and on serum and urine biochemical 

markers of bone turnover. Recruitment of 128 eligible women was completed in December 2003, 

and 118 are under active follow-up. Follow-up will be completed in late 2005 with results in 

presentations and publications in 2006. No serious adverse events have been reported. 

Bone Mineral Density as a Predictor of Periodontitis: The overall goal of this study is to 

determine the role of oral and systemic bone mineral density (BMD) in the development of new 

and progressive periodontal disease in postmenopausal women. Two specific aims are to 

determine if low BMD at specific sites such as the mandible is linked to increased susceptibility 

of tooth loss. The study participants are a cohort of postmenopausal women enrolled in the 

Women’s Health Initiative (WHI) who participated in a cross-sectional study that obtained 

baseline periodontal data. Participants will be followed for three years to assess the temporal 

relationship between BMD and periodontitis. The study completed its second year and is actively 

enrolling women. They have enrolled and completed data collection on 448 women. Their target 

is to enroll 1000 subjects from a total of 1348 eligible postmenopausal women. 

Salivary Biomarkers to Predict Alveolar Bone Loss: The goal of this study is to develop an 

objective, rapid system that can be used with ease in the dental office to identify patients at high 
 

113 

risk for future alveolar bone loss. This information will allow the practitioner to target 

appropriate interventions to patients in most need of treatment and avoid expensive and time 

consuming treatment for patients having limited need for these services. The study will use an 

established method that uses paramagnetic microspheres coated with specific antibodies to 

capture, retrieve, concentrate and identify biomarkers associated with periodontal bone 

destruction in saliva. Additionally, the study will use this technology to also concentrate products 

of bone destruction, such as C-telopeptide pyridinoline crosslinks of Type I collagen (ICTP), 

osteocalcin and osteonectin from human saliva. These concentrated products will then be 

quantitated using simple colorometric methods. These biomarkers, all of which have been 

previously reported to be elevated in gingival crevicular fluid (GCF) of subjects with active 

periodontal disease, in conjunction with other well known risk factors, e.g. age, tobacco use, etc., 

will be used to develop statistical diagnostic models for predicting future alveolar bone loss, 

monitoring patients longitudinally with respect to any periodontal disease status change and 

evaluating treatment success or failure. Saliva, unlike GCF, is readily accessible and can be 

rapidly collected with minimal effort. Thus, this approach could be conveniently adapted in the 

future for use by practicing dentists to provide objective information to assess risk for 

periodontal bone loss.

National Institute of Dental and Craniofacial Research 

Menopause Related Project

Contract or Grant 

Number 

Title Principal 

Investigator 

Institutions 

R01 DE007378 Role of Serotonin in 

Osteoclast 

Differentiation 

Stashencko, 

Philip P 

Forsyth Institute 

R01 DE012872 Low-Dose Doxycycline 

Effects On Osteopenic 

Bone Loss 

Payne, Jeffrey B University of Nebraska Medical 

Center 

R01 DE013505 Bone Mineral Density 

as a Predictor of 

Periodontitis 

WactawskiWende, Jean State University of New York At 

Buffalo 

R21 DE015854 Salivary Biomarkers to 

predict Alveolar Bone 

Loss 

Scannapieco, 

Frank 

State University of New York at 

Buffalo 
 

114 
 

National Institute 

of Diabetes and 

Digestive and 

Kidney Diseases 

(NIDDK) 

115 
 

116 

 

National Institute of Diabetes and 

Digestive and Kidney Diseases 

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) supports 

research on a wide array of diseases and disorders that affect normal metabolism and/or organ 

development and function. These include diabetes, inborn errors of metabolism, endocrine 

disorders, osteoporosis, digestive diseases, obesity, nutritional disorders, hematological diseases, 

and urologic and renal diseases. Determining how and the extent to which menopause uniquely 

influences the onset or course of metabolic disorders and other diseases is important for 

developing appropriate prevention and treatment strategies for these conditions in women; 

equally important are ongoing efforts to prevent or treat those conditions for which menopause is 

a known or apparent “risk factor.” Menopause is marked by dramatic changes in levels of 

gonadal, hypothalamic, and pituitary hormones, which have significant downstream 

physiological effects. Menopause is accompanied by loss of bone calcium, alterations in serum 

lipids resulting in a more atherogenic lipid profile, urogenital atrophy, and redistribution of body 

fat mass. These physiological changes are associated, respectively, with a rapid increase in risk 

for osteoporosis and cardiovascular disease--especially coronary heart disease--and may 

contribute to the increased prevalence of conditions such as urinary incontinence and the 

metabolic syndrome in postmenopausal women. The NIDDK supports basic and clinical 

research relevant to menopause in several areas, including diabetes, obesity and weight 

regulation, endocrinology, osteoporosis, and urologic disorders. The following are examples of 

recently completed or ongoing research relevant to menopause supported by the NIDDK. 

Diabetes

Diabetes Prevention Program Outcomes Study (DPPOS): The Diabetes Prevention Program 

was the first major clinical trial in the U.S. to show that moderate changes in diet and exercise 

can delay and possibly prevent type 2 diabetes in a diverse population of overweight people with 

impaired glucose tolerance (a condition in which blood glucose levels are higher than normal but 

not yet diabetic). The DPP enrolled more than 3,200 participants--68 percent of whom are 

women and 45 percent of whom are from minority groups. The DPP found that modest weight 

loss--5 to 7 percent of body weight--and increased physical activity can cut a person’s risk of 

developing type 2 diabetes by more than half. The DPP also found that the oral diabetes drug 

metformin (Glucophage) reduces type 2 diabetes risk, although not as effectively as lifestyle 

changes. The lifestyle intervention worked equally well in men and women and in all the 

racial/ethnic groups represented in the study. A long-term follow-up study to the DPP, the DPP 

Outcomes Study (DPPOS) is examining the longer-term effects of the trial intervention on the 

development of type 2 diabetes and its complications, particularly cardiovascular disease, in DPP 

participants. It will also compare outcomes for women and men, and by age and ethnicity. 

Other associated health outcomes have been examined in the DPP participants; for example, 

emerging results indicate that the DPP lifestyle intervention had a positive effect on reducing 

prevalence of urinary incontinence in women4

. The long-term effects of the DPP interventions 

on UI and other associated health outcomes will examined in the DPPOS, as well. 

Genetic and Biochemical Predictors of Type 2 Diabetes Mellitus in Women: Diabetes mellitus is 

4 American Diabetes Association 64th Scientific Session, June 4-8, 2004, abstract 983-P.
 

117 

 

a major and increasing public health problem, affecting an estimated 18.2 million Americans, of 

whom 90 to 95 percent have type 2 diabetes5

. A novel hypothesis implicates inflammation and 

endothelial dysfunction in the pathogenesis of type 2 diabetes. Researchers are studying the role 

of several novel and promising biomarkers of inflammation and endothelial dysfunction as 

predictors of risk of type 2 diabetes. In addition, the pathogenic roles of specific genetic markers 

associated with inflammation and endothelial dysfunction are being studied. Elucidation of 

interrelationships between these biomarkers and development of type 2 diabetes may suggest 

new treatment and/or prevention strategies. This study will use samples from 4,300 ethnically 

diverse postmenopausal women free of cardiovascular disease or type 2 DM who are 

participating in the Women's Health Initiative Observational Study Cohort. It will include 

genetic analyses and comparison of data from different ethnic groups in order to improve 

understanding of genetic predictors for future risk of type 2 diabetes in different populations. 

Findings from this and similar studies could shed new light on the etiology of type 2 diabetes, 

especially among minority Americans such as Hispanic/Latinos, Blacks/Africans, and 

Asians/Pacific Islanders who bear a disproportionately high burden of this disease but for whom 

less data is available. (LIU, SIMIN R01 DK062290) 

Estrogens and Insulin Resistance in Women: Estrogen status in premenopausal women may 

protect against fat-induced insulin resistance. This study will use two different approaches to 

test the hypothesis that men and non-hormonally-replaced postmenopausal women are 

vulnerable to fat-induced insulin resistance, while adequately estrogenized women are protected. 

The investigators will also conduct studies with both human participants and mouse models to 

determine whether estrogenization protects women from the insulin resistance induced by 

obesity and aging, including experiments aimed at identifying cellular mechanisms for these 

protective effects of estrogens. The investigators will also seek to determine whether the fat cell 

secreted protein ACRP3O (adiponectin) is modulated by estrogen status, and whether the insulin 

sensitizing effects of ACRP3O are responsible for the estrogen induced protection from insulin 

resistance. Findings from these studies could have significant implications concerning the 

mechanisms of insulin resistance as well as the treatment and possibly prevention of this 

disorder. (OLEFSKY, JERROLD R01 DK061964) 

Complications of Diabetes

Cardiac Risk Factors in Hispanics with Type 2 Diabetes: Cardiovascular disease (CVD) is the 

most common cause of both morbidity and mortality in people with type 2 diabetes. Diabetic 

women have been shown to have a comparable incidence of CVD mortality with diabetic men, 

regardless of age. Apparently, the “protective” effects of estrogen observed in non-diabetic 

women are not observed in diabetic women. Hispanics have shown an increasing incidence rate 

of CVD that is nearly all accounted for by diabetes. Hispanic women with poorly controlled 

type 2 diabetes have been found to have a more atherogenic lipid profile than Hispanic diabetic 

and non-diabetic men. If close control of blood glucose restores the gender differences in CVD 

risk factors, this study could have great implications regarding the treatment of diabetic women. 

(AVILES-SANTA, MAINES K08 DK02606) 

Obesity

5

 National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national 

estimates on diabetes in the United States, 2003. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 

2003. Rev. ed. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2004. 

http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm. 
 

118 

 

Menopause Effect on Obesity, Energy Balance and Insulin: Menopause has been associated with 

changes in body composition and increased cardiovascular risk factors in Caucasian women, 

although less information is available on the effects of menopause in African American women. 

The overall goal of this continuing longitudinal study, the Healthy Transitions Study, is to assess 

the influence of menopause on body composition and fat distribution, and to determine 

mechanisms that may influence body fat changes, in a cohort of Caucasian and African 

American women. Because health statistics for African American women are significantly 

worse than for the U.S. Caucasian population, understanding the effects of menopause on risk 

factors in African American women is of great public health significance. The researchers have 

reported on data from this study indicating that ethnic differences in energy expenditure and the 

intake of certain nutrients may influence the effect of menopausal transition on obesity in 

African American women6

. (SMITH, STEVEN R01 DK050736) 

Gender, Obesity, C-Reactive Protein, and Oxidative Stress: C-reactive protein (CRP), a marker 

of inflammation, is associated with cardiovascular disease, as well as with diabetes and other 

conditions. This study intends to investigate the hypothesis that some of the harmful effects of 

obesity, and of postmenopausal status, are attributable to fat-induced increases in CRP and lipid 

peroxidation. It will test, in a randomized, placebo-controlled trial, whether antioxidant 

supplements can lower CRP levels and reduce tissue damage from lipid peroxidation in 

nonsmokers; whether one antioxidant is significantly more effective than the other; whether 

treatment effects differ by gender or body fat; whether there are gender or body fat differences in 

baseline CRP or in baseline lipid peroxidation, in nonsmokers, independent of other covariates; 

and, in women, whether postmenopausal status is associated with higher baseline CRP or lipid 

peroxidation, after control of covariates. (BLOCK, GLADYS R01 DK062378) 

Sex Steroid, HPA Regulation, and Fat Patterning: Central (visceral) obesity contributes to an 

excess risk of diabetes, dyslipidemia, and death from coronary heart disease in women. Women 

typically express central obesity during menopause but the mechanisms causing this change in 

fat distribution are poorly understood. This investigator has been investigating a possible role 

for estrogen regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the expression of 

visceral obesity in postmenopausal women. One aim of this study is to complete a pilot study 

and to test the ability of estrogen to decrease HPA activity and cortisol levels on a prospective 

basis in postmenopausal women. These studies will provide pilot data for studies of estrogen 

regulation of the HPA axis activity and subsequent changes in body fat distribution in women 

transitioning through the menopause. (PURNELL, JONATHAN R03 DK061996) 

Look AHEAD (Action for Health in Diabetes): This multicenter, randomized clinical trial will 

examine the effects of a lifestyle intervention program designed to promote weight loss through 

reduced calorie intake and regular exercise in 5,145 volunteers. Look AHEAD will examine 

how the lifestyle intervention affects heart attack, stroke, and cardiovascular-related death in 

people with type 2 diabetes--the disease most affected by overweight and obesity. The study will 

recruit individuals between 45 and 75 years of age with type 2 diabetes, who are classified as 

overweight or obese. Women comprise 59.4 percent of participants and at least one third of the 

participants are from racial and ethnic minority groups in the United States. Look AHEAD is 

collecting self-report data on women's health, including questions about history of pregnancies, 

use of hormone medication, and menopausal status. Other sponsoring institutes and 

6

 Lovejoy JC, Champagne CM, Smith SR, de Jonge L, and Xie H. Ethnic differences in dietary intakes, physical activity, and energy expenditure 

in middle-aged, premenopausal women: the Healthy Transitions Study. Am J Clin Nutr. 74:90-5, 2001. 
 

119 

organizations for Look AHEAD include the National Heart, Lung, and Blood Institute (NHLBI), 

National Institute of Nursing Research (NINR), the ORWH, the National Center for Minority 

Health and Health Disparities (NCMHD), and the Centers for Disease Control and Prevention 

(CDC). 

http://www.niddk.nih.gov/patient/SHOW/lookahead.htm

Endocrinology

Pathogenesis and Therapy of Autoimmune Thyroid Disease: Autoimmune thyroid disease 

(AITD) affects at least six percent of all women in their lifetime, and more than ten percent of 

older women. This research program aims to understand the causes of human autoimmune 

thyroid disease, the mechanisms involved in controlling the immune response, and if possible, to 

develop preventive or therapeutic measures based on the immunology of the disease. 

(DEGROOT, LESLIE J. R01 DK027384) 

Menopause, IDDM and Autoimmunity--The FAD Study: The Familial Autoimmune and 

Diabetes (FAD) Study has shown that the prevalence of Hashimoto’s thyroiditis is higher among 

adult women with type 1 diabetes than their non-diabetic sisters or mothers. These findings 

suggest that one’s ability to maintain immunological self-tolerance may be lost prematurely 

among women with type 1 diabetes. This may also reflect one of the many chronic 

complications that occur at an early age among affected individuals. It is expected that other 

indicators of advanced biological age may be common among women with type 1 diabetes. Selfreport data from the FAD study supports this hypothesis. The mean age at menopause for 

women with type 1 diabetes was nearly ten years younger than that for their non-diabetic sisters. 

This appears to be the first formal report of an association between type 1 diabetes and early 

menopause in the literature. Moreover, the public health importance of these data, which must 

be confirmed, is enormous. Given the high incidence of cardiovascular disease and other 

complications known to be associated with long-term diabetes, an early natural menopause is 

likely to exacerbate the risk of myocardial infarction among young women with type 1 diabetes. 

This study will validate the extremely important finding that menopause occurs at a significantly 

younger age among type 1 diabetic women when compared to non-diabetic women. It will also 

evaluate the potential differences in menstrual bleeding patterns, menopausal symptomatology 

and the determinants of age at menopause among type 1 diabetic compared to non-diabetic 

women. In addition, the study will evaluate the effect of the menopause transition on major 

cardiovascular disease risk factors and risk of autoimmune thyroid disease among type 1 diabetic 

compared to non-diabetic women. These researchers recently reported the first set of natural 

history data for the menstrual cycle across all ages of women with type 1 diabetes, which reveals 

a significant increase in menstrual cycle disturbances before age 30 in these women7

. 

(DORMAN, JANICE S. R01 DK044590) 

Bone Loss and Osteoporosis

Pathophysiology of PTH-related Protein (1-36) in Humans: Current treatments for osteoporosis 

focus almost exclusively on agents that inhibit bone resorption. PTH mediates bone formation as 

well as bone resorption, and in clinical studies has shown promise as an osteoporosis treatment. 

Recent studies have demonstrated that human parathyroid hormone-related protein (PTHrP(1-

 

7 Strotmeyer ES, Steenkiste AR, Foley TP Jr, Berga SL, and Dorman JS. Menstrual cycle differences between 

women with type 1 diabetes and women without diabetes. Diabetes Care 26:1016-21, 2003.
 

120 

 

36)) has many properties similar to PTH, can be safely administered to humans. Results from a 

Phase II clinical trial conducted through this project suggest that PTHrP is a pure anabolic agent 

for the treatment of postmenopausal osteoporosis when administered to women on estrogen 

therapy8

. The overall goal of this study is to determine whether PTHrP(1-36) is indeed a potent 

anabolic skeletal agent in humans, if its anabolic effects are maintained in the absence of 

estrogen supplementation, and if it is similar to, or perhaps superior to, PTH in the treatment of 

osteoporosis. Findings from these studies could result in a better understanding of the 

therapeutic potential of PTHrP(1-36). (STEWART, ANDREW F. R01 DK051081) 

Vitamin K and Bone Turnover in Postmenopausal Women: Accumulating data suggest that 

vitamin K (K) insufficiency may contribute to osteoporosis development by causing by causing 

increased bone turnover. However, currently available data do not permit definitive conclusions 

to be drawn regarding a role of K in bone metabolism. The goal of this study is to clarify the 

role of K insufficiency in skeletal health through a prospective, randomized, double-blind, 

placebo controlled trial of K1 supplementation in 226 postmenopausal women. Several 

measures of skeletal turnover will be used to assess the effect of K supplementation on this 

phenomenon. Findings from this study could help inform recommendations for K 

supplementation as part of measures to prevent osteoporosis. (BINKLEY, NEIL C. R01 

DK058363) 

Urinary Tract Health 

Risk Factors for Urinary Tract Infections in Postmenopausal Women: Urinary tract infections 

(UTI) are one of the most common infections in women. Research on the epidemiology and 

etiology of UTI has concentrated on two groups of women--the young and healthy and the 

elderly and debilitated. In elderly women, general debility, voiding problems, diabetes, and 

possibly estrogen deficiency are risk factors. Less is known about risk factors for UTI in women 

soon after menopause. This project has been prospectively evaluating the incidence of acute UTI 

and assessing risk factors for this problem in a cohort of postmenopausal women. The primary 

aims of the study have been to learn the relative effects of diabetes, postmenopausal estrogens, 

urinary incontinence or increased post-void residual urine, and sexual activity on the risk of UTI. 

Recent reports from this group have provided insights into the significance of treated diabetes--

particularly insulin-treated diabetes or diabetes of long duration--history of UTI, and urinary 

incontinence as risk factors for UTIs in healthy postmenopausal women (aged 55 to 75)9

. 

Another study using this cohort (H2O2-Producing Lactobacilli And Postmenopausal UTI) has 

been examining whether changes in the vaginal bacterial flora predispose to UTI in 

postmenopausal women and how various factors, such as diabetes and estrogen therapy, affect 

the vaginal flora. A report on these interrelationships has recently been published10. (FIHN, 

STEPHAN D. R01 DK041341; GUPTA, KALPANA K23 DK2660) 

Risk Factors for Urinary Incontinence in Women: This study has been capitalizing on the 

availability of two large prospective studies of women aged 37-85 years, to examine the 

epidemiology of urinary incontinence (UI) across varying age groups. The investigators have 

8 Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, and Stewart AF: J Clin Endocrinol Metab 88: 569-75, 2003 9 Jackson SL, Boyko EJ, Scholes D, Abraham L, Gupta K, and Fihn SD: Predictors of urinary tract infection after menopause: a prospective 

study. Am J Med. 2004 Dec 15;117(12):903-11. 

Hu KK, Boyko EJ, Scholes D, Normand E, Chen CL, Grafton J, and Fihn SD: Risk factors for urinary tract infections in postmenopausal women. 

Arch Intern Med. 2004 May 10;164(9):989-93

10 Pabich WL, Fihn SD, Stamm WE, Scholes D, Boyko EJ, and Gupta K: Prevalence and determinants of vaginal flora alterations in 

postmenopausal women. J Infect Dis. 2003 Oct 1;188(7):1054-8. 
 

121 

been examining prospectively, through comprehensive questionnaires, the relation of 

reproductive characteristics, menopause, body weight and physical activity, and hormonal factors 

to the incidence of UI, to different types of UI (urge, stress, or mixed incontinence), to its 

severity, its progression, and to its impact on women s daily lives. The investigation utilizes the 

Nurses Health Study and the Nurses Health Study II, observational studies of 121,701 and 

116,678 female nurses, respectively. These two existing cohorts provide a cost-efficient basis 

for conducting a prospective study of UI, allowing better understanding of the epidemiology of 

UI, and identification of preventive strategies. In addition, the establishment of these cohorts for 

studying incontinence will allow future investigations of many other issues, such as the effect of 

diet and various lifestyle habits. The group has recently reported that, in a cohort of nearly 

40,000 participants from the NHS I and II, postmenopausal hormone therapy (irrespective of 

type or route of administration) appears to increase the risk of developing UI11. (GRODSTEIN, 

FRANCINE R01 DK062438) 

Urinary Incontinence Treatment Network (UITN): In community dwelling adults, urinary 

incontinence affects an estimated 35 percent of women 65 years or older and 10 percent of 

women younger than 65 years12. Urinary incontinence, which affects mostly women, is a 

problem often associated with pregnancy, childbirth, menopause, and aging. The UITN was 

established in 1999 in collaboration with the NICHD and with support from the ORWH. The 

purpose of the UITN is to establish a group of collaborating investigators who will conduct longterm studies, including clinical trials, of the most commonly used surgical, pharmacological, and 

behavioral approaches to the management of urinary incontinence in women diagnosed with 

stress and mixed incontinence. The first protocol implemented by the UITN is a randomized 

controlled clinical trial of two surgical procedures commonly used to treat women with stress 

urinary incontinence, the sling and Burch procedures. This ongoing study and other assessments 

will provide both physicians and patients with important information necessary to make wellinformed decisions about the best treatment options. The UITN is currently enrolling patients 

for a second trial, which will focus on treating women with pure or predominantly urge 

incontinence. 

http://www.niddk.nih.gov/patient/uitn/uitn.htm

 

11 Grodstein F, Lifford K, Resnick NM, and Curhan GC. Postmenopausal hormone therapy and risk of developing urinary incontinence. Obstet 

Gynecol. 2004 Feb;103(2):254-60. 

12 Wilson L, Brown JS, Shin GP, Luc KO, and Subak LL. Annual Direct Cost of Urinary Incontinence. Obstetrics and Gynecology. 2001;98:398-

406.
 

122 
 

National Institute 

on Drug Abuse 

(NIDA) 

123 
 

National Institute on Drug Abuse 

Grant Portfolio on Menopause, Aging Women, and Hormone Therapy 

1. ADRIAN DOBS, PI 

Grant Number: R01DA14098-05 

Grant Title: Cognitive Consequences of Endocrine Dysfunction in IDUs 

Purpose: The study will determine the relationship between gonadal milieu and quality of life in IDUs 

infected with HIV; patterns of cognitive performance and QOL; evaluate the safety and efficacy of 

sex hormones replacement therapy on cognitive performance and QOL in men and women. 

Publications: Research suggests that endogenous sex hormones play an important role in regulating 

lipid metabolism in postmenopausal women (Mudali et al. J Clin Endocrinol Metab, 2005, 90(2): 

1202-1209); that there is a reduced bone mineral density in HIV-infected patients and is associated 

with increased central adiposity and postload hyperglycemia (Brown et al. J. Clin Endocrinol Metab. 

2004, 89(3): 1200-1206); and opiate use is a potential contributor to the endocrine and metabolic 

complications in HIV infection (Clin Infect Dis. 2003, 37 Suppl. 2, s132-6). 

• Mudali S, Dobs AS, Ding J, Cauley JA, Szklo M, Golden SH. Endogenous postmenopausal 

hormones and serum lipids: the atherosclerosis risk in cummunities study. J. Clin Endocrinol 

Metab. 2005; 90(2):1202-9.

• Brown TT, Ruppe MD, Kassner R, Kumar P, Kehoe T, Dobs AS, Timpone J. Reduced bone 

mineral density in human immunodeficiency virus-infected patients and its association with 

increased central adiposity and postload hyperglycemia. J. Clin Endocrinol Metab. 2004; 89(3): 

1200-6. 

• Cooper OB, Brown TT, Dobs AS. Opiate drug use: a potential contributor to the endocrine and 

metabolic complications in human immunodeficiency virus disease. Clin Infect Dis. 2003; 37 

suppl 2: s132-6. 

2. ERNEST DRUCKER, PI 

Grant Number RO1 DA11324 

Title of Grant: Office-Based Methadone Prescribing 

Purpose: This grant contains a menopause sub-study. Due to the aging of the heroin-dependent 

population, menopause affects many women in methadone treatment. Menopausal symptoms mimic 

some of the effects of narcotic withdrawal and are easily confused (by both former addicts and 

practitioners) with symptoms related to improper methadone dosage. Yet little attention is currently 

paid to menopausal care and it relationship to methadone dosing within methadone treatment. This 

sub-study is addressing that issue. 

Publication: 

Ellen Tuchman, E. (2004). Methadone and Menopause: Midlife Women in Drug Treatment, Journal 

of Social Work Practice in the Addictions, Vol.3(2), 44-55. [As a rising number of midlife women 

receive methadone treatment, issues related to the menopausal transition take on increased 

importance. The similarity between many of the symptoms associated with opiate withdrawal,

methadone and menopause make it plausible these women and clinical staff attribute menopausal 

symptoms to other conditions of greater familiarity. The paucity of research, multiplicity of health 

problems and typically poor access to health care, further complicate the picture and underscore the 

importance of better integration of health care and social work intervention.]

124 
 

3. JAMES E. FERGUSON, PI 

Grant number: 5 K12 DA014040-05 

Title of grant: Interdisciplinary Research Careers in Women's Health 

Purpose: This program is designed to train junior faculty members ("Scholars") at University of 

Kentucky College of Medicine in interdisciplinary women's health research, and in encouraging their 

research endeavors. The grant is presently focused on 1) drug abuse and its relationship to sex and 

gender differences, 2) cancer as it relates to women's health, 3) hormonal regulation across a woman's 

lifespan, and 4) oral health and its impact on women's cardiovascular and endocrine (diabetes) health 

and on pregnancy outcomes. Program Scholar graduates and their projects include: 

Publications: 

• Dimayuga FO, Reed JL, Carnero GA, Wang C, Dimayuga ER, Dimayuga VM, Perger A, Wilson 

ME, Keller JN and Bruce-Keller AJ. Estrogen and Brain Inflammation: Effects on Microglial

Cytokine Release and MHC/Co-stimulatory Molecule Expression. J Neuroimmunol 161:123-36, 

2005). [Finding: Estrogen decreased components of adaptive immunity in cultured microglial 

cells]

• Wise PM, Smith MJ, Dubal DB, Wilson ME, Rau SW, Cashion AB, Bottner M and Rosewell 

KL. Neuroendocrine modulation and repercussion of female reproductive aging. Recent Prog 

Horm Res 57:235-56, 2002. [Finding: Age-related changes in the ability of estradiol to 

coordinate the neuroendocrine events that lead to regular preovulatory gonadotropin-releasing 

hormone surges contribute to the onset of irregular estrous cycles and eventually to acyclicity. 

Furthermore, the lack of estradiol increases the vulnerability of the brain to injury and 

neurodegeneration.]

• Wilson ME, Liu Y and Wise PM. Estradiol modulates anti-apoptotic signals in the cortical 

explant cultures. Brain Res Mol Brain Res 102:48-54, 2002. [Finding: Estradiol prevents injuryinduced apoptosis, and activation of the serine/threonine protein kinase Akt may mediate these

protective effects.] 

4. ROBERT KLEIN, PI 

Grant Number: 5R01DA14998 

Grant Title: Atherosclerosis/Bone loss/Drug use/HIV in Older Men 

Purpose: The PI is studying: (1) the effect of HIV infection and HAART on the rate and risk factors 

for atherosclerotic disease. Among the risk factors to be considered will be dyslipidemia insulin 

resistance obesity diet and medication and illicit drug and alcohol use; (2) determine the effect of HIV 

infection and HAART on age-related loss of bone mass; (3) determine the effect of HIV infection and 

HAART on high-risk drug using and sexual behaviors of older men. The PI will compare these 

observations with those in older women from their earlier study.

5. MAHENDRA KUMAR, PI 

Grant Number: R01DA13550-01A2 

Grant Title: HIV1 + IDU's--Endocrine Consequences and Medical Outcomes 

Purpose: This study investigates the mediating role of endocrine consequences on the occurrence of 

mental health outcomes (depression, anxiety and perceived psychological distress) in HIV infected 

IDUs. They will investigate the responses of the thyroid and gonads to trophic hormones- thyroid 

releasing hormone (TRH) and luteinizing hormone-releasing hormone (LHRH) as well as adrenal 

activity in response to a low-dose ACTH challenge mainly in African-American and Hispanic men 

and women. 

125 
 

126 

6. NANCY K. MELLO, PI 

Grant Number: 5P01DA014528-4 

Grant Title: Cocaine and Polydrug Abuse: New Medication Strategies 

Purpose: The grant is concerned with cocaine's acute effects on the neuroendocrine system and how 

that contributes to its abuse liability. It includes four inter-related clinical and pre-clinical projects 

designed to facilitate medication development. It relates menopause, older women and/or hormone 

therapy only in that cocaine produces increases in estradiol, testosterone, and luteinizing hormone in 

monkeys with some gender differences. The magnitude of the changes in LH were dependent upon 

baseline differences in estradiol in females. Life cycle changes in hormonal milieu may determine 

the magnitude of hormonal responses to cocaine, which may be related in to its abuse liability and 

changes in menstrual cycle in females. 

Publications: 

• Mello et al., (2004) Effects of cocaine on gonadal steroid hormones and LH in male and female 

rhesus monkeys. Neuropsychopharm. 29: 2024-2034. 

• Caine et al. (2004) Effect of gonadectomy and gonadal hormone replacement on cocaine selfadministration in female and male rats. Neurpsychopharm 29: 929-942. 

• Mello et al. (2004) Ovarian steroid hormone modulation of the acute effects of cocaine on 

luteinizing hormone and prolactin levels in orvariectomized rhesus monkeys. JPET 307-156-167. 

• Negus et al., (2004) Sex differences in thermal nociception and prostaglandin-induced thermal 

hypersensitivity in rhesus monkeys J. Pain 5: 92-103. 

7. JACK H. MENDELSON, PI 

Grant Number: 5 R01 DA15067-03 

Grant Title: Neurobiology of Nicotine: Hormones and Behavior 

Purpose: This study is aimed at investigating the interactions between cigarette smoking and 

menstrual cycle phase. Preliminary data suggest that the subjective and endocrine effects of cigarette 

smoking are greater during the follicular than during the luteal phase of the menstrual cycle. A second 

study's findings suggest that menstrual cycle phase modulates the effects of cigarette smoking on 

mood states and neuroendocrine hormones in women. 

Publications: No publications from this portion of the grant; however, there have been two 

presentations at scientific meetings: 

• Mendelson, J.H., Sholar, M,B., Goletiani, N., Siegel, A.J. and Mello, N,K,. Comparison of the 

effects of cigarette smoking on the hypothalamic-pituitary-adrenal axis and prolactin in follicular 

phase women and men, College on Problems of Drug Dependence, San Juan, PR, 2004. 

• Mendelson, J.H., Sholar, M,B., Goletiani, N., Siegel, A.J. and Mello, N,K,. Menstrual cycle 

phase influences the effects of cigarette smoking on mood states and the HPA axis. American 

College of Neuropsychopharmacology, San Juan, PR, 2004. 

8. ELLIE SCHOENBAUM, PI 

Grant Number: 5R01DA13564-01 

Grant Title: Natural History of Menopause in HIV Infected Drug Users 

Purpose: This study investigates the process of menopause among HIV-infected women and includes 

study of: (1) the impact of HIV infection and drug use on menopausal symptoms and biologic 

markers; (2) attitudes and knowledge about menopause among HIV infected and drug using women 

(3) the impact of H IV infection and drug use on bone mineral density before and after menopause: 
 

and (4) impact of HIV infection and antiretroviral therapy (HAART) on dyslipidemia insulin 

resistance and development of post-menopausal cardiovascular disease. 

9. MEHMET SOFUOGLU, PI 

Grant Number: 5 R01 DA14537-02 

Grant Title: Progesterone and the Effects of Nicotine 

Purpose: The menstrual cycle phase may affect smoking behavior and the severity of tobacco 

withdrawal symptoms in female smokers. It has been observed that progesterone treatment may 

attenuate the subjective effects and craving for cigarettes. This is a double-blind, placebo-controlled 

study in which male and female smokers will be randomly assigned to one of the 3 treatment 

conditions: placebo, low (200 mg/day) or high dose (400 mg/day) of progesterone for four days. The 

investigators hypothesize that progesterone treatment, dose-dependently, will reduce smoking 

behavior, attenuate tobacco withdrawal symptoms, and subjective rewarding effects of smoking in 

both male and female smokers. This study may provide a better understanding of the mechanisms, 

which mediate the sex and menstrual cycle phase effects on nicotine dependence. 

10. DANIEL SOLOMON, PI 

Grant Number: 1R01DA15507 

Grant Title: Pain Medication Use & Risk Factors for Opioid Dependence 

Purpose: This grant will examine the extent and determinants of chronic prescription opioid use 

problems among Medicare patients who are diagnosed as having osteoarthritis or rheumatoid arthritis. 

Prescription opioid abuse will be examined in a community-based cohort of 250,000 Medicare 

patients who receive prescription drug benefits from the Pennsylvania Department of Aging's 

Pharmaceutical Assistance Contract for the Elderly (PACE). All eligible patients are over 65. The 

sample is 81% female. 

Publications: 

• Fischer MA, Schneeweiss S, Avorn J, Solomon DH. Medicaid prior-authorization programs and 

the use of cyclooxygenase-2 inhibitors. N Engl J Med. 2004 Nov 18;351(21):2187-94. 

BACKGROUND: Over the past five years, selective cyclooxygenase-2 inhibitors (coxibs) have 

accounted for a growing proportion of prescriptions for nonsteroidal antiinflammatory drugs 

(NSAIDs). To control these expenses, many state Medicaid programs have implemented priorauthorization requirements before coxibs can be prescribed. This study evaluated the effect of 

such programs on the use of coxibs by Medicaid beneficiaries. METHOD: Using data for all 

filled prescriptions in 50 state Medicaid programs from 1999 through the end of 2003, the 

researchers calculated the proportion of defined daily doses of NSAIDs accounted for by coxibs. 

Time-series analyses were used to measure the changes in prescription patterns after the 

implementation of each prior-authorization program. RESULTS: By 2001, coxibs accounted for 

half of all NSAID doses covered by Medicaid. This proportion varied widely according to the 

state in 2003, from a low of 11 percent to a high of 70 percent of all NSAID doses. Twenty-two

states implemented prior-authorization programs for coxibs during the study period. Overall, the 

implementation of such programs reduced the proportion of NSAID doses made up by coxibs by 

15.0 percent (95 percent confidence interval, 10.9 to 19.2 percent), corresponding to a decrease of 

10.28 dollars (95 percent confidence interval, 7.56 dollars to 13.00 dollars) in spending per 

NSAID prescription. 

• Solomon DH, Avorn J. Pharmacoepidemiology and rheumatic diseases: 2001-2002. Curr Opin 

Rheumatol. 2003 Mar;15(2):122-6. Pharmacoepidemiology is the branch of epidemiology that

focuses on medications and their outcomes, including both adverse events and intended 

consequences. Such studies have become more prominent in rheumatology as the number of new 

medications has grown and prescribing databases have become more available. In the past year, 

127 
 

the potential cardiovascular complications associated with selective COX-2 inhibitors have 

become an important concern. A number of pooled analyses suggest the possibility of an 

increased risk of acute myocardial infarction, and studies of naproxen have found a possible 

protective effect. Accumulating evidence supports the contention that early initiation of disease 

modifying antirheumatid drug therapy improves outcomes of patients with rheumatoid arthritis. 

Open-label extensions of biologic therapies found continued benefits extending several years with 

the TNF-alpha antagonists, but concerns have arisen regarding tuberculosis and central nervous 

system demyelination with these agents. Data continue to be published quantifying the risk of 

osteoporosis associated with glucocorticoids, and the association between biphosphonate therapy

and upper gastrointestinal events appears to be less of a concern that originally described. 

128 
 

National Institute of Environmental 

Health Sciences 

(NIEHS) 

129 
 

130 

NIEHS GRANTS RELATED TO MENOPAUSAL TRANSITION 

FY2004 

F32ES11941 Pru, James K. Massachusetts General Hospital 

Control of Maternal-Fetal Interaction by PAS Genes 

Abstract: The aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT) and 

hypoxia-inducing factor-la (HIF-l a) are members of the Per/Arnt/Sim (PAS) family of proteins 

that regulate transcription of target' genes in response to physiological (e.g., endogenous signals) 

and pathological (e.g., environmental toxicants) cues. Interestingly, PAS family members, 

including the AHR and ARNT, are constitutively expressed in many tissues, including those of 

the female reproductive system. Of relevance to this application, expression of the AHR and 

ARNT at uterine implantation sites (fetal and maternal interfaces), coupled with the fact that 

Ahr-deficient female mice have reduced litter sizes, suggest that the members of the PAS family 

have a biological function during pregnancy. Moreover, chemical Iigands of the AHR, such as 

polycyclic aromatic hydrocarbons (PAH) derived from the incomplete combustion of fossil fuels 

and tobacco smoke, have been implicated from both epidemiological and animal studies to have 

deleterious effects on pregnancy. Computer-based sequence analysis of a number of genes 

previously shown to be functionally required for the establishment of pregnancy and 

decidualization, in addition to novel genes regulated by the embryo (presented herein), has 

revealed that the promoters of many of these genes harbor AHR response elements. Such 

findings are in keeping with results from Dr. Tilly's lab using PAH-exposed ovaries in gene 

profiling experiments (microarrays), Which identified many of these same genes as being 

putative targets for the AHR. Based on these observations, it is hypothesized that PAS family 

members serve as key regulatory switches to coordinate the expression of specific genes in the 

uterus during pregnancy, both in response to the decidualization process and in response to an 

embryonic-derived factor(s). Of particular interest for consideration of PAS transactivation are 

the genes cylooxygenase-2, prostaglandin '2 synthase, peroxisome proliferator-activated 

receptor- and retinoic acid X receptor a (general decidualization process), and acid 

sphingomyelinase and interferon stimulated gene 15 (induced by the embryo). Furthermore, the 

candidate also hypothesizes that environmental toxicants, such as PAH, alter the expression of 

these genes in a manner incompatible with the establishment or maintenance of pregnancy. As 

such, results from the proposed experiments will not only shed new light on the role of PAS 

family members and their target genes in embryo implantation and pregnancy, but also how the 

magnitude and temporal aspects of this expression must be precisely coordinated for pregnancy 

to occur.

Publications: 

Takai Y, Canning J, Perez GI, Pru JK, Schlezinger JJ, Sherr DH, Kolesnick RN, Yuan J, Flavell RA, 

Korsmeyer SJ, Tilly JL. Bax, caspase-2, and caspase-3 are required for ovarian follicle loss caused by 4-

vinylcyclohexene diepoxide exposure of female mice in vivo. Endocrinology. 2003 Jan;144(1):69-74. 

P30ES00002 Brain, Joseph D. Harvard School of Public Health 

HSPH NIEHS Center for Environmental Health 
 

131 

Abstract: Our Center fosters active collaborations among three Research Cores: 1) Metals, 2) 

Urban and Occupational Particles, and 3) Organic Pollutants. The work of the Research Cores is 

greatly enhanced by three Facility Cores: 1) Biological Analyses, 2) Exposures and 

Environmental Analyses, and 3) Environmental Statistics. Finally, the investigators' ability to 

make their research and knowledge available to the public is greatly enhanced by the Community 

Outreach and Education Program (COEP). Other Center activities, such as pilot projects, new 

investigators, and program enrichment are catalytic mechanisms to achieve integration, 

interaction, productive, and innovative science. The objectives of this NIEHS Center are to 

generate new knowledge relating to the physiology, pharmacology, pathology, cell biology, 

molecular biology, genetics, and epidemiology of environmental disease, and to apply this 

knowledge to new modalities of prevention, diagnosis, and therapy. The investigators achieve 

these objectives through a variety of approaches, which range from studies of molecules and 

cells to those of whole animals and human populations. Through the organizational structure and 

financial support provided by the NIEHS Center Grant, the investigators' will increase the impact 

of their research and teaching in environmental health. In toto, the Harvard NIEHS Center for 

Environmental Health continues to be a major focal point for environmental research and 

training in Boston. The NIEHS Center mechanism enhances connections and makes the Harvard 

NIEHS Center part of a national and international network. 

Publications: 

Garrido Latorre F, Hernandez-Avila M, Tamayo Orozco J, Albores Medina CA, Aro A, 

Palazuelos E, Hu H. Relationship of blood and bone lead to menopause and bone mineral density 

among middle-age women in Mexico City. Environ Health Perspect. 2003 Apr;111(4):631-6. 

P30ES06694 Liebler, Daniel C. University of Arizona 

Southwest Environmental Health Sciences Center 

Abstract: Through the NIEHS Center Core Grant Program the University of Arizona Center for 

Toxicology will develop the Southwest Environmental Health Sciences Center (SWEHSC), at 

the University of Arizona. The EHSC will be a major component of the University of Arizona 

Center for Toxicology, which was established by the Arizona Board of Regents in 1987. The 

mission of the EHSC is to integrate, coordinate and expand interactions among a group of 

established investigators conducting high quality research in the area of environmental health 

sciences. This mission will be fulfilled by fostering interdisciplinary approaches to understanding 

mechanisms by which environmental chemicals impact human health and to identifying factors 

that affect these mechanisms. Thirty-two SWEHSC Investigators have formed four 

interdisciplinary Research Programs that represent current research activities and provide the 

basis for new research initiatives. These Programs are Biotransformation, Metals, Cell Injury and 

Environmental Genetics. To increase productivity and enhance the quality of research being 

conducted in each of these Research Programs, three Service Cores (Synthetic Chemistry, 

Analytical Services, Experimental Pathology) have been formed. These cores will offer certain 

routine services and assist investigators in introducing new methodologies into their research. In 

addition to the three Service Cores, a Transgenic Animal Facility will be developed within the 

Environmental Genetics Research Program. The Administrative Core will provide enrichment 

programs for SWEHSC investigators through seminars and workshops, recruit new SWEHSC 

Investigators both from within and outside the University of Arizona, promote opportunities for 

innovative research ideas through the Pilot Projects Program, and oversee all activities. The 

Community Outreach and Education Program will encourage students, particularly minority 
 

132 

students to consider careers in environmental health; establish collaborative research and 

education programs in Mexico; and offer programs in environmental sciences to health related 

professionals. The SWEHSC will be a regional representative of NIEHS serving citizens in the 

Southwest. Because of the proximity of this area to Mexico and collaborative interactions to 

develop environmental health science programs in that country, SWEHSC will have a positive 

health impact on citizens on both sides of the border. 

Publications: 

Mayer LP, Pearsall NA, Christian PJ, Devine PJ, Payne CM, McCuskey MK, Marion SL, Sipes 

IG, Hoyer PB. Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene 

diepoxide. Reprod Toxicol. 2002 Nov-Dec;16(6):775-81. 

P30ES07049 Peters, John M. University of Southern California 

Environmental Exposures, Host Factors and Human Disease 

Abstract: This application is to continue our Southern California Environmental Health 

Services Center whose main purposes are 1) to study the effects of environmental exposures on 

humans; 2) to determine host factors (genetic and other) influencing response to these exposures; 

and 3) to inform the public. To accomplish these goals we bring together an interdisciplinary 

team of investigators from 2 major Souther California universities: USC and UCLA. The 

research of our Center features interdisciplinary cornerstones: detained exposure assessment, 

including toxicokinetics and biomarkers; cutting edge study design, including the most powerful 

statistical and epidemiologic approaches; and the basic sciences, including physiology, molecular 

biology, genetics, chemistry and engineering. The foci of the Center cover a wide range of 

problems and address environmental exposures of public health importance including indoor and 

outdoor air pollution, pesticides, alflatoxins, radiation, passive smoking, bioaerosols and nitrites. 

The 5 Research Cores consist of: Respiratory Effects; Exposure Assessment; Childhood Cancer, 

Adult Cancer Study Design and Statistical Methodology. The 3 Facility Cores consist of: the 

Molecular Biology, Sample Processing and Storage Core; the Analytic Chemistry, Exposure 

Assessment and Aerosol Sciences Core; and the Biostatistics Core. The Center also features a 

separate core for Community Outreach and Education (COEP). The Center is structured to 

promote interdisciplinary research and linkage between the research and the COEP. Processes 

creating these interactions include the seminar series, pilot projects, research focus groups, 

workshops and retreats. The first 4 years of support for this Center have resulted in recruitment 

of new investigators, more investigators working on environmental health problems, doubling of 

funding support, more interaction between researchers from different disciplines and a greater 

production of research findings relevant to answering critical public health questions. The Center 

also developed research initiatives for the next 5 years that focus the interdisciplinary team of 

investigators on important environmental health problems involving genetic-environmental 

interactions as asthma and cancer. 

Publications: 

Ursin G, Tseng CC, Paganini-Hill A, Enger S, Wan PC, Formenti S, Pike MC, Ross RK. Does 

menopausal hormone replacement therapy interact with known factors to increase risk of breast 

cancer? J Clin Oncol. 2002 Feb 1;20(3):699-706. 
 

133 

Pike MC, Ross RK. Progestins and menopause: epidemiological studies of risks of endometrial 

and breast cancer. Steroids. 2000 Oct-Nov;65(10-11):659-64. 

P30ES10126 Swenberg, James A. University of North Carolina at Chapel Hill 

UNC-CH Center for Environmental Health & Susceptibility 

Abstract: The focus of this "UNC-CH Center on Environmental Health and Susceptibility" is in 

the area of environmental epidemiology and toxicology. Three research cores will form the 

intellectual heart of the Center, organized around the following areas of concentration: Genetic 

Susceptibility, bringing together laboratory and molecular epidemiologic research on genomic 

determinants of susceptibility; Developmental Susceptibility, addressing the role of different 

stages in the life cycle and how these influence susceptibility to exposure, with a particular 

concentration on exposures received from conception through childhood; and Toxicokinetic 

Susceptibility, reexamining inter-individual variability in physiologic and metabolic factors that 

are responsible for the wide ranges in response to an exogenous agent. Four facility cores will 

provide critical services and will result in cost-efficiency for Center investigators: High 

Throughput Genotyping, Biostatistics and Epidemiologic Methods, Biomarkers, and Nutrient 

Assessment. The Administrative Core will have responsibility for coordination of Center 

activities, strategic planning and evaluation: the Pilot Projects Program; membership decisions; 

financial matters; leadership and visibility for UNC-CH's environmental health research. The 

Community Education and Outreach Program will assist the Administrative Core in 

dissemination and education about Center- related themes on environmental health to 

professionals, the media, and the public at large, with a focus on the state of North Carolina, and 

will promote two-way scientist/citizen interactions. This Center is designed to maximize crossdisciplinary integration to promote new research collaborations with exciting scientific potential, 

understand the mechanistic basis of chemical toxicity, and effectively reduce the burden of 

environmentally-related disease. 

Publications: 

Gaudet MM, Britton JA, Kabat GC, Steck-Scott S, Eng SM, Teitelbaum SL, Terry MB, Neugut 

AI, Gammon MD. Fruits, vegetables, and micronutrients in relation to breast cancer modified by 

menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev. 2004 

Sep;13(9):1485-94

R01ES08430 Tilly, Jonathan L. Massachusetts General Hospital 

Mechanisms of Aryl-Hydrocarbon-Induced Ovotoxicity 

Abstract: Polycyclic aromatic hydrocarbons (PAH) are released into the environment by fossil 

fuel combustion. Another primary route of human exposure to PAH is cigarette smoke. Evidence 

that PAH cause premature ovarian failure has been provided by both epidemiological and animal 

studies. However, the mechanisms by which PAH damage the ovary have remained obscure for 

decades. These chemicals are particularly intriguing as there exists an intracellular binding 

protein for PAN termed the aryl hydrocarbon receptor (AHR). The AHR is a basic helix-loophelix transcription factor that regulates gene expression following ligand interaction and nuclear 

translocation. During the previous funding cycle of this grant, the P1 completed experiments to 

validate the central hypothesis that PAN-mediated activation of the AHR in oocytes induces 

apoptosis by increasing expression of the gene encoding Bax, a pro-apoptotic member of the bcl-
 

134 

2 gene family. However, several new questions arose during these studies. First, does the AHR 

function to set the "apoptosis susceptibility" of female germ cells by transcriptional regulation of 

cell death regulatory genes in addition to bax? Second, is the inability of dioxin, a known AHR 

ligand, to damage the ovary related to differences in AHR response element (AHRE) flanking 

sequences in "target" cell death regulatory genes (e.g., bax) that convey specificity for PAHAHR versus dioxin-AHR interactions? Third, does the induction of bax gene expression in 

oocytes require an AHR-interacting protein(s) that permits AHR-bax gene promoter interaction? 

Based on preliminary data presented herein, the PT has hypothesized that PAH-AHR. but not 

dioxin-AHR, interaction transcriptionally sets the cell death susceptibility "rheostat" in female 

germ cells to favor apoptosis. This is accomplished via a coactivator(s) expressed in oocytes that 

facilitates functional interaction between the PAN-activated AHR and cell death regulatory gene 

promoters possessing AHRE. To test this hypothesis, the following Specific Aims are proposed 

for continuation of these studies: 1) to determine if expression of the pro-apoptotic bak gene is 

increased in oocytes exposed to PAN, if PAN-AHR interaction is required for increased 

transcriptional activity of the bak gene, and if expression of the endogenous bak gene is required 

for the ovotoxic effects of PAN; 2) to examine if the expression patterns of a number of key 

apoptosis regulatory genes, known to be expressed in oocytes, are altered by AHR deficiency 

and/or by PAH-driven AHR activation; 3) to produce a gene expression profile for AHR initiated 

cell death signaling in oocytes using a microscale gene array technology recently developed for 

small biological samples; 4) to delineate the role of nucleotide sequences flanking the "core" 

five-nucleotide AHRE in the bax gene promoter in specifying responses to the AHR activated by 

PAN versus dioxin; and, 5) to identify AHR-interacting proteins in oocytes, using matrixassisted laser desorption and ionization/time-of-flight mass spectrometry (MALDI/TOF-MS), 

that may be involved in specifying cell lineage-selective induction of bax gene transcription by 

the PAN-activated AHR. 

Publications: 

Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, Laine J, Sakai T, 

Korsmeyer SJ, Casper RF, Sherr DH, Tilly JL. Aromatic hydrocarbon receptor-driven Bax gene 

expression is required for remature ovarian failure caused by biohazardous environmental 

chemicals. Nature Genet. 2001 Aug;28(4):355-60. 

Tilly JL, Kolesnick RN. Sphingolipids, apoptosis, cancer treatments and the ovary: investigating 

a crime against female fertility. Biochim Biophys Acta. 2002 Dec 30;1585(2-3):135-8. Review. 

Morita Y, Perez GI, Paris F, Miranda SR, Ehleiter D, Haimovitz-Friedman A, 

Fuks Z, Xie Z, Reed JC, Schuchman EH, Kolesnick RN, Tilly JL. Oocyte apoptosis is 

suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate 

therapy. Nature Medicine. 2000 Oct;6(10):1109-14. 

Takai Y, Canning J, Perez GI, Pru JK, Schlezinger JJ, Sherr DH, Kolesnick RN, Yuan J, Flavell 

RA, Korsmeyer SJ, Tilly JL. Bax, caspase-2, and caspase-3 are required for ovarian follicle loss 

caused by 4-vinylcyclohexene diepoxide exposure of female mice in vivo. Endocrinology. 2003 

Jan;144(1):69-74. 

R01ES09246 Hoyer, Patricia B. University of Arizona 

Signaling Pathways in Chemical Induced Ovotoxicity 
 

135 

Abstract: Women are exposed daily in the workplace, as well as the environment (cigarette 

smoke, automobile exhaust) to chemicals that can damage small pre-antral (primordial) ovarian 

follicles. Damage to these follicles can result in early ovarian failure (menopause). Because 

menopause is associated with a variety of health disorders, this represents a plausible health risk. 

Dosing of mice and rats with the occupational chemical, 4-vinyl-cyclohexene diepoxide (VCD) 

destroys primordial follicles and early ovarian failure can be caused in rodents by repeated 

dosing. On-going mechanistic studies in rats have helped characterize VCD as a model chemical 

for the study of xenobiotic-induced destruction of primordial follicles. However, the exact 

mechanisms which initiate oocyte degeneration remain unknown. Thus, it is proposed here to 

expand the base of mechanistic information obtained with VCD to further identify those 

mechanisms. Because a variety of environmental chemicals are known to destroy primordial 

follicles, VCD-related information will prove applicable to chemicals that are sources of greater 

exposure in the environment. The hypothesis to be tested is that VCD causes destruction of 

primordial follicles by upregulation of pre- and post-transcriptional intracellular pathways and 

the extent of this destruction is modulated by introvarian xenobiotic metabolizing capabilities. 

The Specific Aims are to: (1) identify and characterize gene expression directly regulated by 

VCD dosing, (2) dissect signaling pathways involved in VCD-induced ovotoxicity (3) 

characterize the ability of ovarian compartments to bioactivate and detoxify VCH, VCME, and 

VCD. Specifically investigating the mechanism(s) by which VCD damages ovarian primordial 

follicles will provide a greater ability to predict potential risks for early menopause from 

exposures to ovotoxic environmental chemicals in women. This greater awareness will lead to an 

appreciation of the global impact of the environment on age of menopause in women. 

Publications: 

Mayer LP, Pearsall NA, Christian PJ, Devine PJ, Payne CM, McCuskey MK, Marion SL, Sipes 

IG, Hoyer PB. Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene 

diepoxide. Reprod Toxicol. 2002 Nov-Dec;16(6):775-81. 

Hoyer PB, Devine PJ, Hu X, Thompson KE, Sipes IG. Ovarian toxicity of 4-vinylcyclohexene 

diepoxide: a mechanistic model. Toxicol Pathol. 2001 Jan-Feb;29(1):91-9. Review. 

R01ES12238 Whitsel, Eric A. University of North Carolina at Chapel Hill 

The Environmental Epidemiology of Arrythmogenesis in the Women’s Health Initiative 

Abstract: Air pollution and cardiovascular disease mortality are clearly linked, yet populationbased studies of air pollution and arrhythmogenesis have not been conducted in women. 

Moreover, extant studies have not evaluated whether acute, pro-arrhythmic effects of exposure to 

ambient air pollutants are modified by three potentially important markers of the environmental, 

socioeconomic and clinical context within which such exposures ostensibly increase 

cardiovascular risk in women: chronic exposure status, neighborhood of residence, and diseasespecific susceptibility factors for sudden death. We will investigate these issues in an ethnically 

diverse population of 68,133 post-menopausal women aged 59-70 years from the 40 clinical 

centers and their satellites participating in the baseline examination of the Women's Health 

Initiative clinical trial (WHI, 1993-1998). We will estimate exposure to criteria pollutants 

(PM10; NO2; SO2; CO; 03) in ambient air at geocoded participant addresses using validated, 

spatial models that rely on pollutant concentrations recorded at adjacent fixed-site monitors in 
 

136 

the U.S. Environmental Protection Agency Aerometric Information Retrieval System. Spatially 

interpolated exposures will take the form of average pollutant concentrations on the day of, and 

for the 1, 2 & 3 days and 1, 2 & 3 years preceding the baseline examination and year three 

follow-up. We will reliably evaluate autonomic function, atrioventricular conduction, ventricular 

depolarization, ventricular repolarization and ectopy from resting, standard 12-lead ECGs 

recorded at the WHI examinations. After removing seasonal variations and long-term trends, and 

in addition, adjusting for demographic and meteorological covariates, we will explore the 

putative association between air pollutants and ECG measures. Then we will determine whether 

the associations are modified by chronic exposure status, socioeconomic characteristics of 

geographic regions in which participants live, and clinical risk factors for sudden cardiac death 

using Bayesian, hierarchical models. Lastly, we will assess sensitivity of our findings to 

adjustment for exposure measurement error arising from spatial interpolation of personal 

exposures from ambient concentrations of air pollutants. Our ancillary study will thereby 

evaluate the biologically relevant proarrhythmic mechanisms and contextual features linking 

ambient air pollution to cardiovascular disease morbidity and mortality in a large, ethnically and 

geographically diverse group of postmenopausal women. In doing so, it will improve 

understanding of associations between airborne pollutants and cardiovascular disease mortality, 

facilitate assessment of current U.S. air quality standards, and yield insight into the relatively 

gradual decline of sudden cardiac death rates among U.S. women over the last decade. 

Publications: None 
 

NIEHS Menopause Related Research 2004 

 

Grant Number PI Name Project Title

 

Menopause 

1Z01ES049026-08 COOPER, GLINDA Menstrual Patterns, Menopause, and Women's Health

1Z01ES040012-05 GLADEN, BETH Organochlorines and their human health effects

2R01ES009246-05A1 HOYER, PATRICIA Signaling Pathways in Chemical Induced Ovotoxicity

1Z01ES049030-08 SANDLER, DALE Health Effects Of Exposures In Agriculture

1Z01ES049013-10 BAIRD, DONNA Uterine Leiomyomas

5R01ES007171-09 ESKENAZI, BRENDA Female Reproductive Outcomes and TCDD Exposure in 

Seveso

5R01ES012238-02 WHITSEL, ERIC The Environmental Epidemiology of Arrythmogenesis in WHI

1U01ES012800-010001 HASLAM, SANDRA Environmental Effects on the Molecular Architecture

1R15ES012182-01 MAY, JEFFREY Neonatal Endocrine Disruption and Ovarian Senescence

5K08ES010963-04 LUDERER, ULRIKE GSH: Protecting Ovarian Follicles from Oxidant Injury

5R01ES008430-08 TILLY, JONATHAN L. Mechanisms of Aryl-Hydrocarbon-Induced Ovotoxicity

1Z01ES100327-02 MURPHY, ELIZABETH Mechanism Of Cardioprotection In Females

5R21ES012272-02 GORE, ANDREA Neuroendocrine outcomes of prenatal PCB exposures

 

Aging Women 

5P30ES007033-109010 FAUSTMAN, ELAINE Core--Reproductive and Developmental Toxicology

5R21ES012272-02 GORE, ANDREA Neuroendocrine outcomes of prenatal PCB exposures

1R01ES012916-01 PETROFF, BRIAN Aryl hydrocarbon receptor pathway and reproductive aging

1R21ES013061-01 FLAWS, JODI Long-term Consequences of Fetal Endocrine Disruption

5R01ES012238-02 WHITSEL, ERIC The Environmental Epidemiology of Arrythmogenesis in WHI

1Z01ES049013-10 BAIRD, DONNA Uterine Leiomyomas

1Z01ES049026-08 COOPER, GLINDA Menstrual Patterns, Menopause, and Women s Health

1R15ES012182-01 MAY, JEFFREY Neonatal Endocrine Disruption and Ovarian Senescence

 

Hormone Therapy and Women 

5R01ES009418-07 SHIBUTANI, SHINYA Genotoxicity of Estrogen-and Anti-estrogen-DNA Adducts

1Z01ES049013-10 BAIRD, DONNA Uterine Leiomyomas

1Z01ES025034-10 ZELDIN, DARRYL Characterization & Functional Significance Of P450s

1Z01ES070065-28 KORACH, KENNETH Chemical Receptor Interactions In Reproduction And Hormo

1Z01ES100327-02 MURPHY, ELIZABETH Mechanism Of Cardioprotection In Females

137 
 

138 
 

National Institute 

of General 

Medical Sciences 

(NIGMS) 

139 
 

National Institute of General Medical Sciences 

Menopause Related Research 2004

Title Menopause, Symptoms, Blood Pressure and Health Risk in Hawaii’s Multiethnic 

Population 

Principal Investigator: Daniel E. Brown, Ph.D. 

Grant Number: S06-GM008073 

Priority Score: 202 

MPRC-B Workgroup 4 

DESCRIPTION (provided by applicant): Women’s risk of cardiovascular disease increases 

upon menopause. Hot flashes, a common symptom associated with menopause, lead to both 

discomfort and elevated blood pressure. There are population differences in the age at which 

menopause is reached and in the frequency with which symptoms associated with menopause are 

reported. The current study proposes to examine ethnic differences in the age at menopause and 

experience of hot flashes in Hawaii’s multiethnic population. The project has three components: 

a mailed survey of a random sample of adult women in Hilo Hawaii (N=1500), which includes 

questions about demographics, health and menopausal experience: an ambulatory monitoring of 

blood pressure and skin conductance over a 24-hour period of in a subsample (N=200) of these 

women that will also include collections of a blood sample for lipid analysis; and a laboratory 

investigation of objective and subjective measures of hot flashes and their physiological 

concomitants in the subsample of women under conditions that often induce hot flashes. Two 

study hypotheses are that there are significant ethnic differences in the percentage of women who 

report experiencing hot flashes, and that the peri- and post-menopausal women who report 

experiencing hot flashes will have higher mean daily B and elevated sleeping BP relative to 

same-age women who do not, or rarely, experience hot flashes. The implication of the research 

is that differences in the experience of menopause and its symptoms in peri- and postmenopausal 

women may explain some of the ethnic variation in cardiovascular health risk. 

140 
 

National Institute of 

Mental Health 

(NIMH) 

141 
 

142 

National Institute of Mental Health 

Menopause Related Research 2004 

Neuroprotective effects of estrogen in brain 

Estrogen receptor (ER) activation has been shown to protect neurons in a number of different studies. However, it is 

unclear what the roles of the different types of estrogen receptor (ER alpha and ER beta) are in neuroprotection. To 

address this question, the investigators examined the impact of selective ER agonists for either ER alpha or ER beta 

to prevent the death of hippocampal neurons exposed to a toxin. Results indicated that both receptor subtypes could 

be involved in estrogen neuroprotection. As ER beta is highly expressed in the brain and has little or no expression 

in the breast or uterus, discovery and design of ER beta selective molecules could provide a strategy for activating 

the beneficial effects of estrogen in the brain without activating untoward effects of estrogen in reproductive organs. 

Zhao L, Wu TW, Brinton RD. Estrogen receptor subtypes alpha and beta contribute to neuroprotection and 

increased Bcl-2 expression in primary hippocampal neurons. Brain Res. 2004 Jun 4;1010(1-2):22-34. 

Estrogen modifies neuronal structure through novel mechanisms. 

Estrogen (E) treatment induces branching of neurons in the hippocampus (an area of the brain involved in memory 

formation) of the rat. Results of this study showed that estrogen treatment of mice caused an increase in neuronal 

spine processes and molecular markers of increased neuronal synaptic communication within a subset of neurons of 

the hippocampus. These structural changes were associated with improved performance on a spatial episodic 

memory task. Taken together, the results suggest a previously uncharacterized role for estrogen in altering neuronal 

communication that is associated with enhancement of hippocampal-dependent memory. 

Li C, Brake WG, Romeo RD, Dunlop JC, Gordon M, Buzescu R, Magarinos AM, Allen 

PB, Greengard P, Luine V, McEwen BS. Estrogen alters hippocampal dendritic spine shape and enhances synaptic 

protein immunoreactivity and spatial memory in female mice. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2185-

90. 

Akama KT, McEwen BS. Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein 

kinase B pathway. J Neurosci. 2003 Mar 15;23(6):2333-9. 

Estrogen receptor beta selective SERMS have antidepressant action in preclinical test 

This study examined the actions of selective estrogen receptor modulators (SERMs) with different affinities for the 

intracellular estrogen receptor (ER) alpha or beta isoforms in a rodent behavioral test used to screen for 

antidepressant activity. Data from these studies suggest that estrogenic antidepressive effects may involve actions at 

ERbeta. 

Walf AA, Rhodes ME, Frye CA. Antidepressant effects of ERbeta-selective estrogen receptor modulators in the 

forced swim test. Pharmacol Biochem Behav. 2004 Jul;78(3):523-9. 

Estrogen treatment increases serotonin 2A receptors in postmenopausal women 

In animal models, estrogen has been shown to influence serotonin receptors. Modulation of serotonin may be one 

way that estrogen affects mood and cognition. In this study, investigators examined the effect of estrogen on brain 

serotonin 2A receptors through the use of positron emission tomography (PET) scans in postmenopausal women to 

see whether there was any correlation of receptor changes with cognition and mood. Serotonin receptor binding was 

significantly increased after estrogen replacement in prefrontal areas of the brain. Verbal fluency and Trail Making 

Test performance, but not mood, were significantly improved by estrogen without correlation with receptor changes. 

Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, Staley JK, Garg PK, Seibyl JP, Innis RB. 

Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women. Am J 

Psychiatry.2003 Aug;160(8):1522-4. 

Relationship between menopausal hormone status and depression 

Mood and reproductive function were prospectively evaluated in asymptomatic premenopausal women to determine 

whether the onset of depression was temporally linked to the perimenopause. Women followed through the onset of 

menopause with both hormonal and mood measures showed an increased risk of depression during the 24 months 
 

143 

surrounding the final menses, indicating that the late perimenopause may be a time of increased susceptibility to 

develop depression in some women. In a separate study, researchers examining the role of ovarian function and 

mood during the perimenopause, found that when ovarian function increased (demonstrated by higher lower levels 

of FSH) that mood improved in women with perimenopausal depression. 

A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. 

Schmidt PJ, Haq N, Rubinow DR. Am J Psychiatry. 2004 Dec;161(12):2238-44.

Concordant restoration of ovarian function and mood in perimenopausal depression. Daly RC, Danaceau MA, 

Rubinow DR, Schmidt PJ. Am J Psychiatry. 2003 Oct;160(10):1842-6 
 

144 

NIMH Menopause Related Research 2005

Full Grant Number Division PI Name Project Title 

1Z01MH002537-15 IRP SCHMIDT, PETER J 

PSYCHOBIOLOGY AND TREATMENT 

OF PERIMENOPAUSAL MOOD DISOR 

1Z01MH002648-12 IRP CHIUEH, CHUANG C

NEUROPROTECTIVE STRATEGIES

AGAINST BRAIN DISORDERS CAUSE 

1Z01MH002659-12 IRP GOLD, PHILIP W

THE NEUROBIOLOGY OF MAJOR 

DEPRESSION 

1Z01MH002765-08 IRP RUBINOW, DAVID

REPRODUCTIVE ENDOCRINE

RELATED MOOD DISORDERS 

5K08MH001682-05 DNBBS

ALTEMUS, 

MARGARET 

ESTROGEN EFFECTS ON ANXIETY 

RELATED NEURAL SYSTEMS 

5R01MH059689-06 DMDBA

BROMBERGER, 

JOYCE T 

MENOPAUSAL TRANSITION, 

MENTAL HEALTH AND ETHNICITY 

7R01MH059891-05 DNBBS FOSTER, THOMAS C 

ESTROGEN AND COGNITION OVER 

THE LIFESPAN 

5R01MH059919-05 DNBBS PARRY, BARBARA L

MENOPAUSAL DEPRESSION: 

CHRONOBIOLOGIC BASIS 

5R01MH059970-07 DNBBS SHORS, TRACEY J

STRESS AND MEMORY FORMATION 

ACROSS THE FEMALE LIFESPAN 

5R01MH060858-04 DNBBS LERANTH, CSABA

ESTROGENIC EFFECT ON 

HIPPOCAMPAL THETA RHYTHM

AND MEMORY 

5R01MH061817-03 DNBBS HERNDON, JAMES G

SELECTIVE ESTROGEN

MODULATORS AND COGNITION

5R01MH062677-04 DNBBS BETHEA, CYNTHIA L

OVARIAN STEROID REGULATION OF 

SEROTONIN IN PRIMATES

5R01MH063089-03 DNBBS

FREEDMAN, 

ROBERT R 

SLEEP DISTURBANCE IN 

MENOPAUSE

5R03MH063932-02 DNBBS ECKEL, LISA A

MECHANISM OF ESTROGEN'S

INHIBITORY EFFECTS ON FEEDING 

5R03MH065460-02 DNBBS FRICK, KARYN M 

ESTROGENIC-CHOLINERGIC 

INTERACTIONS IN MEMORY 

MODULATION

5R01MH065990-02 DNBBS

COHEN, ROCHELLE

S. 

ESTROGEN AND CAM KINASE IV IN

THE LIMBIC SYSTEM 

5K23MH066978-02 DMDBA JOFFE, HADINE

PHYSIOLOGY OF ESTROGEN'S MOOD 

EFFECT IN MENOPAUSAL WOMEN 

1R01MH067602-01A1 DNBBS 

MELTZER, 

CAROLYN C. 

AGE/SEX EFFECTS ON THE CENTRAL 

SEROTONIN SYSTEM 

jsp/dataview0/dat
 

145 

1R01MH069732-01A1 DMDBA 

HARLOW, BERNARD 

L 

RISK FOR NEW ONSET OF 

DEPRESSION IN PERIMENOPAUSAL 

WOMEN 

1R03MH069780-01 DNBBS AKAMA, KEITH T 

NON-GENOMIC ACTIONS OF 

ESTROGEN ON SYNAPSE FUNCTION. 

1R21MH069810-01A1 DNBBS CALDWELL, JACK D

CHARACTERIZATION OF CENTRAL 

ABP/SHBG RECEPTORS 

1R21MH070003-01A1 DNBBS ARNSTEN, AMY F.T. 

ESTROGEN, STRESS AND 

DYSFUNCTION OF PREFRONTAL 

CORTEX 

1F32MH070086-01A1 DNBBS JASNOW, AARON M 

NEUROENDOCRINE MECHANISMS 

OF EMOTIONAL BEHAVIOR 

1F31MH071085-01A1 DNBBS 

COFER SMITH, 

CAROLINE D 

ESTROGEN MODULATES 

HIPPOCAMPAL MORPHOLOGY AND 

PLASTICITY 

Grant: 1Z01MH002537-15 

Program Director:

Principal Investigator: SCHMIDT, PETER J N/A

Title: PSYCHOBIOLOGY AND TREATMENT OF PERIMENOPAUSAL MOOD DISOR 

Institution: N/A 

The goal of this project has been to examine the central nervous system effects of changes in 

reproductive endocrine function occurring in the context of hypogonadism. Investigations have 

been primarily focused on the characterization of affective disorders occurring during the 

perimenopause and midlife, the identification of the role of gonadal steroids in these mood 

disorders, and the examination of the neuroregulatory consequences of the presence and absence 

of gonadal steroids in women and men. Finally, the information obtained by these protocols will 

help identify the predictive utility of endocrine measures in perimenopausal depression and help 

define the role of hormonal therapies in mood disorders occurring at midlife in men and women. 

Findings to date: 1) a significant improvement in measures of depression and libido after DHEA 

administration was seen in 46 men and women with midlife-related major and minor depression; 

2) neither gender nor plasma hormone levels predicted the therapeutic response to DHEA 

administration in midlife-related depression; 3) neither short term (six week) nor long term (six 

months-one year) administration of DHEA significantly altered measures of bone metabolism or 

bone density; 4) seven of 13 depressed perimenopausal women have experienced a remission of 

their depression during participation in a double-blind placebo-controlled trial of estradiol, 

phytoestrogens, and SERMs; 5) the SERM raloxifene was associated with an increase in plasma 

estradiol levels and a remission of mood symptoms in three (of three) perimenopausal depressed 

women. In a study involving the induction of hypogonadism in men and women with GnRH 

agonists, we have observed the hypogonadal state to be associated with the following: 1) the 

development of clinically significant mood symptoms in approximately 10% of hypogonadal 

men despite the presence of hot flushes and loss of libido in 90-100% of these men; 2) baseline 

evaluations of sexual functioning but not plasma hormone levels predicted the degree to which 
 

sexual function was decreased after induced hypogonadism in both men and women (higher 

baseline sexual functioning was associated with greater declines in libido during hypogonadism); 

3); CSF measures of the neurosteroid androsterone but not testosterone correlate with sexual 

function in men during both hypogonadism and testosterone replacement; and 4) the elimination 

in women of both cognition activated regional cerebral blood flow (O15 3D PET scans) in the 

dorsolateral prefrontal cortex and the reciprocal functional connectivity between the left

hippocampal formation and the contralateral dorsolateral prefrontal cortex compared to either 

estradiol or progesterone replacement. In collaboration with NICHD we have observed that 

women with Turner Syndrome (n = 100) have significantly higher scores on measures of 

shyness, depression and anxiety than asymptomatic controls (n = 35) but their scores do not 

differ from those in women with premature ovarian failure (POF) (n =100). Finally, women with 

POF report an increased frequency of past episodes of depression compared to community 

samples of women, and the majority of these depressive episodes occurred in the context of 

menstrual cycle irregularity preceding their final menstrual period and the diagnosis of POF. 

Grant: 1Z01MH002648-12

Program Director:

Principal Investigator: CHIUEH, CHUANG C N/A 

Title:

Institution: N/A

NEUROPROTECTIVE STRATEGIES AGAINST BRAIN DISORDERS CAUSE 

Thioredoxin (Trx) is a multifunctional anti-oxidative and anti-apoptotic redox protein. We 

recently demonstrated that Trx can be induced by preconditioning procedures and drugs such as 

l-deprenyl and 17beta-estradiol. For managing progressive neurodegeneration such as 

Alzheimer's dementia and Parkinson?s disease we proposed to investigate the novel signaling 

pathway of NOS1-cGMP-PKG for increasing cytoprotective genes and antiapoptotic genes. 

Recent clinical trials of hormone replacement therapy indicated that hormone therapy's risks out 

weighed their benefits. These recent clinical reports are at odds with most of the recent 

preclinical studies; most of basic studies infer that estrogen and 17beta-estradiol may produce 

beneficial actions in the brain. Significant side effects of stroke, cancer and blood clots have 

been previously documented in clinical trials of contraceptive pills containing estrogen and 

progestin; most young women are willing to take risks over unwanted pregnancies. Menopausal 

women suffering from severe estrogen withdrawal symptoms may also need to make this kind of 

difficult decision. We investigated elusive actions of estrogen in the brain, which are likely 

mediated by nuclear estrogen receptors ERalpha and ERbeta. We employed 17beta-estradiol for 

investigating whether estrogen protects against neurodegeneration in human cell models. 

Physiological concentrations of 17beta-estradiol activate nuclear estrogen receptors 

(ERbeta>ERalpha) and up-regulate cGMP-dependent Trx expression. Moreover, l-deprenyl 

activates the signaling pathway of NO-cGMP-PKG also confers significant neuroprotection 

possibly through the induction of the redox protein Trx. Our collaborative integrated research 

project on neuronal adaptation, gene expression, and redox proteomics supports a new 

hypothesis that induction of NOS1 gene may result in cyto-and neuro-protection via induction of 

both antioxidative and anti-apoptotic proteins. Human SH-SY5Y cells were sensitive to 

oxidative stress-induced apoptosis since they contain relatively low levels of Trx. When these 

neurotrophic cells were subjected to a non-lethal preconditioning stress (2-hour serum

deprivation), their NOS1 and Trx were up-regulated, and the cells became more tolerant of 

146 
 

oxidative stress with significant neurite extension, indicating that NO may compensatorily 

protect cells from free radical-induced apoptosis and result in neurotrophic cells with 

synaptogensis. In the present study, the contribution of Trx to the preconditioning mechanism by 

which NO/GSNO exerts its neuroprotective effects (hormesis) was investigated. Our results 

revealed that in addition to estrogen, l-deprenyl GSNO inhibits apoptosis through its ability to 

activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). 

The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit 

caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1, Trx, and Bcl-2. 

The induction of survival proteins was down stream to the signaling pathway of phosphorylated 

MAPK/ERK1/2, and c-Myc. Moreover, elevation of Trx, Trx peroxidase-1 and MnSOD 

inhibited oxidative stress and free radical generation. Interestingly, exogenously administered 

Trx also increased the synthesis of Bcl-2 and MnSOD leading to inhibition of lipid peroxidation 

and apoptotic cell death. Preconditioning-induced hormesis is mediated by the elevation of 

NOS1, NO, and cGMP, plus the biosynthesis of the redox protein Trx and associated Bcl2, 

MnSOD and trophic factors. For achieving neuroprotection, multi faceted therapeutics derived 

from Trx may be more effective than using large doses of a single antioxidant. 

Grant: 1Z01MH002659-12

Program Director:

Principal Investigator: GOLD, PHILIP W N/A

Title: THE NEUROBIOLOGY OF MAJOR DEPRESSION

Institution: N/A

There are virtually no incontrovertible data elucidating the pathophysiology of the premature 

mortality, coronary artery disease, or osteoporosis seen in major depression. This is, of course, 

first and foremost an issue of patient survival and quality of life. Compelling data regarding 

pathophysiolgical mechanisms will also help formally establish major depression as a systemic 

disease in the general medical community. This, in turn, will elicit the surveillance of the 

medical community for systemic abnormalities in depressed patients, and the institution of 

effective preventive interventions to mitigate these systemic abnormalities. Contributing to this 

task could help highlight the urgency of diagnosing and treating depression, reduce the stigma of 

depression, and make it imperative for insurance companies to treat depression like any other 

systemic disease. We have identified an emerging metabolic syndrome in young, lean remitted 

patients with major depression, as well as premature osteoporosis, and are well on the way to 

ascertaining dysregulations among important mediators that could lead to the premature death 

and to both systemic manifestations. We found that compared to 47 BMI matched controls, 

remitted, young, lean patients with a major depressive illness had insulin resistance, increased 

plasma insulin, glucose, and triglyceride levels, as well as other serious sequella of insulin 

resistance and hyperinsulinism. Insulin exerts many adverse effects that are adaptive during 

acute stress but maladaptive when sustained. Insulin stimulates the secretion of proinflammatory 

cytokines such as IL-6, procoagulant compounds such as factor VIII, antifibrinolytic compounds 

such as PAI-1, and activates the sympathetic nervous system. We have found increased aroundthe-clock plasma IL-6 levels, and increased morning levels of factor VIII and PAI-1 levels, and 

unequivocal indices of sympathetic activation (the latter in patients with melancholic

depression). It is of interest that both IL-6 and NE promote osteoporosis and coronary artery 

disease. One of our corollary goals is to identify common pathophysiolgical features that are 

147 
 

involved in both premature osteoporosis and coronary artery disease. This work could also 

extend concepts of the metabolic syndrome as a syndrome that includes both the metabolic 

abnormalities cited above as well as pathologic bone loss. Our finding of continuous elevations 

of plasma IL-6 levels has several implications. IL-6 has pleotropic effects and itself causes 

insulin resistance, increased inflammation, increased clotting, and decreased fibrinolysis. IL-6 is 

implicated as a highly significant factor in both atherosclerosis, which has a strong inflammatory 

component, as well and osteoporosis. Plasma IL-6 levels in healthy individuals are the best 

predictor of subsequent coronary artery disease, exceeding C-reactive protein (CRP) in its 

predictive value. IL-6 levels also predict osteoporosis, and IL-6 is among the most potent inducer 

of bone resorption. In the post-menopausal period, one of the important mechanisms posited for 

this condition is the loss of estrogen-mediated suppression of IL-6 release. We also found that a 

group of unmediated depressed patients with melancholic depression had high, around-the-clock 

central and peripheral hypersecretion of NE, as well as of plasma epinephrine, and cortisol 

secretion. While depressed, they also had increased blood pressure and pulse rates; all were 

reversible by a centrally directed treatment, ECT. CSF NE, plasma NE, and plasma cortisol rose 

and fell together throughout the 24 hour period, and rose progressively during EEG-documented 

sleep, peaking in the early morning, the time of the highest incidence of sudden death and 

myocardial infarction. Plasma EPI levels were also very high at this point, as were plasma IL-6 

levels in our former study. Central NE activatiion and peripheral hypersecretion of plasma NE, 

EPI, and cortisol are all cardiotoxic, and their rising and falling together throughout the 24 hour 

period could have a particularly adverse effects. In addition, patients with chronic heart failure 

complicated by depression have a doubling of morbidity and mortality. NE levels no higher than 

in our depressed patients were the best predictor of subsequent mortality and morbidity in 

chronic heart failure. This finding provides a mechanism for the deleterious effect of depression 

when superimposed upon another systemic disease. We first found that premenopausal women 

with major depression have a marked increase in the prevalence of osteopenia and osteoporosis. 

Compared to 3-4% of the general premenopausal population, we found a 20-25% of osteopenia 

or osteoporosis in our depressed patients. Extrapolating from our data, we estimate that over 

400,000 premenopausal women with major depression have osteopenia or osteoporosis as a 

consequence of their depression. Unfortunately osteoporosis is a silent disease until a fracture 

occurs. It is, however, a highly treatable illness, highlighting the need for early detection. The 

incidence of osteopenia and osteoporosis in premenopausal women is alarmingly high, and a 

significant public health hazard. In summary, depression increases premature mortality, coronary

artery disease, and osteoporosis. Our group conducting a program of clinical and translational 

research to ascertain the pathophysiology of these phenomena. 

148 
 

149 

Grant: 1Z01MH002765-08 

Program Director:

Principal Investigator: RUBINOW, DAVID N/A 

Title: REPRODUCTIVE ENDOCRINE RELATED MOOD DISORDERS--DIFFERENT 

Institution: N/A 

Gonadal steroids are major neuroregulators and presumably underlie gender-related differences 

(sexual dimorphisms) in brain structure and function. We have studied reproductive endocrinerelated mood disorders as well as developed endocrine models for these disorders in order to 

characterize the role of gonadal steroids in affective disturbance. Our major recent findings are 

as follows: 1) Extension and confirmation of our preliminary demonstration that continuous 

administration of combined estradiol and progesterone eliminates premenstrual syndrome in the 

context of ovarian suppressive therapy (i.e., it is the change in hormones that precipitates 

depression in this subgroup); 2) Evidence from our ovarian suppression protocol that women 

with a history of non-puerperal depression resemble women with premenstrual dysphoria (PMD) 

in that the introduction of reproductive steroids precipitates a depression; 3) Demonstration that 

the HPA axis [CRH-stimulated ACTH and exercise-stimulated cortisol] is upregulated in men 

compared with women under hypogonadal conditions, (thus contradicting assumptions that 

observed dimorphisms were consequent to activational effects of gonadal steroids); 4) Evidence 

that gonadal steriods have different regulatory effects on the HPA axis in men and women, with 

testosterone decreasing (men) and progesterone increasing (women) CRH-stimulated cortisol; 5) 

Women with PMS metabolize progesterone differently from control women, with the decrease in 

allopregnanolone levels during continuous progesterone administration associated with symptom 

development in women with PMS but not controls. These observations are of both theoretical 

and practical import. They more precisely define the physiologic trigger of PMS and help 

identify the physiological modulators of the HPA axis (which is disturbed in PMS). Additionally, 

the data with continuous hormone administration may not only inform our understanding of the 

relevant hormonal stimuli that precipitate PMS, but as well may suggest a new therapeutic 

strategy for the millions of women who suffer from this disorder. 

Grant: 5K08MH001682-05 

Program Director: DESMOND, NANCY L 

Principal Investigator: ALTEMUS, MARGARET MD 

Title: ESTROGEN EFFECTS ON ANXIETY RELATED NEURAL SYSTEMS 

Institution: WEILL MEDICAL COLLEGE OF CORNELL UNIV NEW YORK, NEW YORK

DESCRIPTION: (Adapted from the Investigator's Abstract) This Mentored Clinical Scientist 

Development Award, a program of research and career development, is proposed to establish a 

foundation for future independent research in behavioral neuroscience, with a focus on 

reproductive hormones and emotional regulation. The research component of the proposal is a 

series of studies investigating the hypothesis that estrogen restrains fear associated behaviors. 
 

Clinical data indicates that reproductive hormones fluxes have profound effects on the course of 

anxiety disorders and depression, but the neurobiological determinants of these clinical 

observations are not well understood. The specific aims of the research plan are to: 1) study the 

effects of estrogen on a battery of behavioral tests of anxiety; 2) examine the effects of estrogen 

on glucocorticoid and stress induced enhancement of fear behaviors; 3) examine the effects of 

estrogen on extrahypothalamic CRH and glucocorticoid receptors, a neuroendocrine system

known to modulate fear and anxiety and 4) define the anatomic sites of estrogen action on fear 

behaviors. Fear associated neural circuits involving the amygsala, bed nucleus of the stria 

terminalis, and medial prefrontal cortex will be studied using local administration of estrogen 

and estrogen antagonists. The training portion of this proposal consists of basic neuroscience 

coursework and seminars as well as hands-on instruction in behavioral analysis and functional 

neuroanatomic techniques. Studies of the effects of estrogen on anxiety related neural systems 

provides an opportunity for the investigator to expand her area of expertise from clinical 

neuroendocrinology and clinical psychiatry to behavioral neuroscience where the effects of 

hormones on brain function can be studied more directly. This field of investigation is likely to 

improve understanding and treatment of anxiety and affective disorders, both of which are 

widely prevalent, chronic public health problems. 

Grant: 5R01MH059689-06

Program Director: OTEY, EMELINE M. 

Principal

Investigator: BROMBERGER, JOYCE T PHD 

Title: MENOPAUSAL TRANSITION, MENTAL HEALTH AND 

ETHNICITY 

Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH, 

PENNSYLVANIA 

DESCRIPTION (provided by applicant): This competing renewal application is a revision of 

what was previously a Collaborative R0l three site prospective study of middle-aged women's 

mental health that is an ancillary study of the Study of Women' Health Across the Nation 

(SWAN). Due to difficulty with retention and feasibility issues at the other 2 sites they will be 

unable to continue the study. We are proposing to continue the study in Pittsburgh only. Our 

current sample consists of 412 African American and Caucasian women, aged 42-52 at the start 

of the study in 1996, who are beginning or will soon begin the menopausal transition. Women 

are interviewed annually with the Structured Clinical Interview (SCID) for DSM-IV Axis I 

Disorders. Our specific aims are: 1) to assess whether women will be more likely to develop a 

new (recurrent) syndromal or subsyndromal depression during the perimenopausal transition 

than before or after, 2) to determine if a history of major depression (MOD) is risk factor for the 

following during the transition: (a) syndromal or subsyndromal depression, (b) increased levels 

of perceived stress, somatic and psychological symptoms, or (c) decreased quality of life or 

functioning and 3) to compare rates of new (recurrent) syndromal or subsyndromal depression 

across the transition for African American and Caucasian women. The longitudinal nature of the 

SWAN biological and psychosocial data (e.g., medical morbidity, stressful events, lifestyle 

behaviors) will allow us to evaluate these as antecedents, correlates, and consequences of 

depression during the course of the study. By continuing to collect systematically psychiatric 

data in our cohort in conjunction with the continued collection of Core SWAN data, we have a 

unique opportunity to expand knowledge of women's mental health in midlife and beyond. 

150 
 

Grant: 7R01MH059891-05

Program Director: ANDERSON, KATHLEEN C.

Principal Investigator: FOSTER, THOMAS C PHD 

Title: ESTROGEN AND COGNITION OVER THE LIFESPAN

Institution: UNIVERSITY OF FLORIDA GAINESVILLE, FLORIDA 

The long-term goals of this research are to understand the mechanisms for the decline in 

hippocampal-dependent memory function during aging. The incidence of Alzheimer s disease is 

projected to nearly quadruple in the next 50 years with the greatest prevalence in women. 

Importantly, estrogen treatment can delaying the progression of memory loss associated with 

aging and Alzheimer s disease. However, little is known concerning which of the many estrogen 

associated effects on brain function are important for memory. The discovery of several different 

estrogen receptors (Ers) within the hippocampus makes this challenge more formidable. Recent 

studies suggest that age- related memory impairment is due to changes in the threshold for

synaptic modification thought to underlie memory storage processes. In turn, threshold changes 

are linked to altered Ca2+ homeostasis during aging. Interestingly, the influence of estradiol (E2) 

on Ca2+ homeostasis is diametrically opposed to the changes observed in aged memory impaired 

animals. The proposed studies test the hypothesis that E2 effects on memory are due to changes 

in the susceptibility to synaptic modification as a result of altered Ca2+ homeostasis processes. 

The proposal has three specific aims. First we will characterize the effects of E2 replacement, at 

physiologically relevant doses, on tasks that are sensitive to hippocampal-dependent memory 

function. In addition, these studies will employ female Eralpha knockout mice to determine 

whether Eralpha activation is involved in E2 mediated effects on memory. Second, we will test 

the hypothesis that E2 effects on memory are mediated by changes in the thresholds for synaptic 

plasticity. It is predicted that the frequency-response function for synaptic plasticity is 

transformed by E2 replacement due to a shift in the threshold for synaptic modification, and 

memory function will correlate with synaptic plasticity. Thirdly, we will test the hypothesis that 

E2 mediated changes in synaptic modification are due to nongenomic mechanisms that rapidly 

regulate Ca2+ homeostasis and cell excitability. For these studies, the effect of E2 on the Ca2+-

dependent processes including synaptic plasticity will be examined in the hippocampal slice. We

believe that the results of our experiments will add significantly to our knowledge concerning the

regulation of synaptic function across the life span and provide a basis for understanding the 

mechanism for estrogen s effects of memory. 

Grant: 5R01MH059919-05

Program Director: BRADY, LINDA S.

Principal Investigator: PARRY, BARBARA L MD 

Title: MENOPAUSAL DEPRESSION: CHRONOBIOLOGIC BASIS

Institution: UNIVERSITY OF CALIFORNIA SAN DIEGO LA JOLLA, CALIFORNIA

No Abstract Available

151 
 

Grant: 5R01MH059970-07

Program Director: LEDERHENDLER, ISRAEL I 

Principal

Investigator: SHORS, TRACEY J PHD 

Title: STRESS AND MEMORY FORMATION ACROSS THE FEMALE 

LIFESPAN 

Institution: RUTGERS THE ST UNIV OF NJ NEW BRUNSWICK NEW BRUNSWICK, NEW 

JERSEY 

DESCRIPTION (provided by applicant): It has become increasingly clear that males and females 

differ even more dramatically than we previously thought. Not only do they exhibit differing 

responses to stress and environmental experience, but they can also respond in opposite 

directions. In rats, exposure to an acute stressful event enhances associative learning in males 

while dramatically impairing performance in females (Wood et al 2001, Wood & Shors 1998; 

Shors et al., 1998, 2002). These opposite effects of stress on memory formation are accompanied 

by similarly opposite effects on the presence of dendritic spines in the hippocampal formation 

(Shors et al 2001). Moreover, these opposite effects of stress are mediated by different hormonal 

systems between the sexes (Wood et al 2001, Beylin & Shors 2002). Sex differences usually 

arise from activational and organizational effects of sex hormones which fluctuate across the 

lifespan, especially in females. The experiments described in this competing continuation 

capitalize on hormonal fluctuations and changes in emotionality that occur during very early 

development, puberty, post-partum and menopause. They are designed to associate and 

dissociate changes in learning ability and responses to stressful experience with changes in 

hormones and density of dendritic spines in the hippocampal formation. Finally, experiments are 

designed to explore a potential relationship between sex differences in learning and the 

expression of growth hormone (GH) in the hippocampus, a gene that is preferentially induced by 

learning (Donahue et al., 2002). Techniques include trace eyeblink conditioning in the rat, Golgi 

impregnation and light microscope analysis, real-time polymerase chain reaction, in situ 

hybridization, radioimmunoassay, and surgical manipulation of glucocorticoids and ovarian 

hormones. Overall, these studies will identity the neuronal and hormonal mechanisms that 

underlie sex differences in learning and opposite responses to stressful experience in males 

versus females. Because mental disorders often emerge or are exacerbated during these life 

changes, the studies will provide insight into sex differences in mental illness, especially those 

experienced so frequently by women: post-traumatic stress disorder (PTSD), unipolar, postpartum and post-menopausal depression, as well as Alzheimer's disease. 

Grant: 5R01MH060858-04

Program Director: ANDERSON, KATHLEEN C.

Principal

Investigator: LERANTH, CSABA MD 

Title: ESTROGENIC EFFECT ON HIPPOCAMPAL THETA RHYTHM 

AND MEMORY

Institution: YALE UNIVERSITY NEW HAVEN,

CONNECTICUT

152 
 

DESCRIPTION: (Adapted from applicant's abstract): Recent evidence indicates that estrogen 

treatment in ovariectomized rats enhances performance on memory tasks. Similarly, human 

observations suggest a beneficial effect of estrogen treatment on cognitive function in 

Alzheimer's disease. However, those cellular targets of gonadal hormones that are directly 

involved in memory processes are ill defined. The only solid observations are that systemic 

hormonal manipulations result in changes in the density of spines and alterations in the intensity 

of immunostaining for NMDA receptor of hippocampal CAl pyramidal cells. However,

hippocampal principal neurons themselves do not, only a small population of interneurons 

contains nuclear estrogen receptor. On the other hand, neurons in subcortical areas, including the 

medial septum diagonal band of Broca (MSDB), supramammillary area (SUM), and median 

raphe (MR) contain nuclear estrogen receptors, and these structures are associated with the 

generation/regulation of hippocampal theta activity and long term potentiation. Furthermore, 

hippocampal theta activity, which is greatly influenced by the changing levels of circulating 

estrogen, in conjunction with long-term potentiation is believed to be involved in memory 

processes. Therefore, the hypothesis that estrogen, in addition to influencing the hippocampus 

directly, regulates mnemonic processes by affecting these subcortical areas will be tested by 

experiments designed to examine the effects of intra-MR, -MSDB, and -SUM administration of 

estrogen in ovariectomized rats on: 1) changes in dendritic spine density of hippocampal CAl 

pyramidal cells; 2) mRNA and peptide levels of ionotropic glutamate receptors in the 

hippocampus; 3) hippocampal theta activity. 

Grant: 5R01MH061817-03

Program Director: WINSKY, LOIS M.

Principal Investigator: HERNDON, JAMES G PHD 

Title: SELECTIVE ESTROGEN MODULATORS AND COGNITION

Institution: EMORY UNIVERSITY ATLANTA, GEORGIA

Estradiuol (E2) replacement therapy (ERT) in menopausal women has protective effects on a 

variety of age-related diseases, including osteoporosis, cardiovascular diseases, age-related 

memory impairments, and development of dementia. However, ERT, even with progestin cotreatment, induces precancerous changes in the tissues of the breast and uterus. A new group of 

non-steroidal estrogens, deemed Selective Estrogen Receptor Modulators (SERMs) has been 

developed as a possible alternative to ERT but without the adverse proliferative effects on breast 

and endometrial tissues, while retaining some of the positive effects of E2. Yet, despite the welldocumented efficacy of these compounds in peripheral target tissues, their influence in the brain, 

and especially upon cognitive function, is not known. Clearly brain and cognitive effects of 

SERMs must be understood in order to determine their desirability as an alternative to ERT in 

hypoestrogenic women. We will use the ovariectomized rhesus monkey as a model of human 

low-estrogen conditions, such as menopause, to examine the effects of SERMs on female 

cognition. This project will first determine whether the SERMs tamoxifen and raloxifene are E2 

agonists or E2 antagonists in a variety of cognitive domains in Ovariectomized female rhesus 

monkeys. Monkeys will be repeatedly tested with a computerized touch- screen system on a 

battery of four memory and attentional tasks while undergoing E2, SERMs, or placebo 

treatments. Specific Aim 2ill use the same battery of tasks to determine whether SERMs, in the 

presence of E2, act as E2 antagonists on cognitive function. Specific Aim 3 will use positron 

emission tomography (PET) and the glucose metabolic tracer [18F]fluorodeoxyglucose (18F 

153 
 

FDG) to determine whether E2 increases activation of specific brain regions following 

performance on the cognitive task most improved by ERT. Specific Aim 1 will determine 

whether SERMs mimic E2 in enhancing object recognition memory, attention, and working 

memory, while impairing spatial memory functions in ovariectomized female rhesus monkeys. 

Specific Aim 2 will determine whether SERMs, in the presence of E2, act a sE2 antagonists in 

cognitive function/ Specific Aim 3 will use PET and the 18F FDG tracer to evaluate the 

relationships between rCMRglc, ERT, and cognitive performance on a specific task. These data 

in the rhesus monkey will provide valuable information on the efficacy of SERMs on female 

cognition and will help in evaluating the risks and benefits of using these compounds in 

hypoestrogenic women. 

Grant: 5R01MH062677-04

Program Director: WINSKY, LOIS M.

Principal Investigator: BETHEA, CYNTHIA L PHD 

Title: OVARIAN STEROID REGULATION OF SEROTONIN IN PRIMATES 

Institution: OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND, OREGON

DESCRIPTION (applicant's abstract): The previous interest of this laboratory in the neural 

regulation of progestin-induced prolactin secretion in primates has evolved into a broader interest 

in the regulation of serotonin neural function by ovarian steroids. The serotonin neural system

projects to nearly every area of the forebrain and serotonin plays a major role in the regulation of 

numerous autonomic and cognitive neural processes. Thus, understanding the action of ovarian 

steroids in the serotonin neural system has relevance to many aspects of mental health and 

function in women. This proposal continues our search, at a cellular and molecular level, for 

neural targets of progesterone (P) which are unique from the action of estrogen (E) and it 

initiates studies to determine the mechanism by which E exerts differential effects on the 

expression of 3 pivotal genes: tryptophan hydroxylase (TPH), the serotonin reuptake transporter 

(SERT), and the 5-HT1A autoreceptor, in serotonin neurons of macaques. The overall hypothesis 

is that progesterone (P) has unique, undiscovered, genomic actions in the serotonin neural system

which elevate 5-HT neurotransmission. Estrogen (E) is required for the induction and 

maintenance of nuclear P receptors and E alone changes the expression of pivotal genes related 

to serotonin synthesis, uptake, and neuronal firing. The molecular actions of E may be mediated 

by ER-beta and could involve a protein-protein interaction with nuclear factor kappa B (NF-kB). 

Aim 1 will obtain definitive evidence that addition of P to an E regimen increases serotonin 

neurotransmission by application of microdialysis and measurement of serotonin in the 

extracellular compartment of terminal fields in steroid-treated macaques. Aim 2 will determine 

the functional consequences of previously reported changes in TPH, SERT, and 5-HT1A 

autoreceptor gene expression in serotonin neurons of macaques treated with E and P. Aim 3 will 

determine the effect of E and P on degradative mechanisms of serotonin. Gene expression and 

function of monoamine oxidase (MAO-A) will be determined in the dorsal raphe and 

hypothalamic termina1 field. Aim 4 will seek the expression of ER-beta and determine if nuclear 

factor kappa B (NF-kB) is co-expressed and regulated by E or P in serotonin neurons of 

macaques. Aim 5 will use laser capture to obtain pure populations of serotonin neurons from

steroid-treated macaques and amplify their RNA for examination of genes related to 

phosphorylation events. These experiments will (1) further the hypothesis that E and P increase 

154 
 

serotonin neural function and (2) initiate investigations of the mechanism of action of E and P in 

serotonin neurons. 

Grant: 5R01MH063089-03

Program Director: BABCOCK, DEBRA J. 

Principal Investigator: FREEDMAN, ROBERT R PHD 

Title: SLEEP DISTURBANCE IN MENOPAUSE

Institution: WAYNE STATE UNIVERSITY DETROIT, MICHIGAN

At present, over 35% of the women in the United States have reached the median age of 

menopause, 51 years. Hot flashes (HFs) are the most common symptom of the climacteric and 

occur in the vast majority of postmenopausal women. Sleep disturbance has also been reported to 

be highly prevalent in this population. Yet, the causal links, if any, between these 2 phenomena 

are I not known. In the studies proposed here, we will attempt to discern the relationships among 

Hfs and objective and subjective sleep disturbance. In Study 1, we will record sleep and HF 

parameters in postmenopausal women with HFs, those without HFs, and age-matched 

premenopausal women without HFs. We will perform quantitative EEG analyses, use an 

objective test of daytime sleepiness (MSLT) and assess subjective sleep quality with established 

instruments. HF frequency increases with ambient temperature. If HFs produce arousals and 

thereby disrupt sleep, then reducing ambient temperature should improve sleep and increasing 

temperature should worsen it (Study 2). Increased arousal frequency has been found in 

postmenopausal women with HFs. If this accounts for reports of poor sleep, then experimental 

sleep disruption in asymptomatic women should produce reports of poor sleep, as well. In Study 

3, we will use yoked groups of symptomatic and asymptomatic women and disrupt sleep of the 

latter group based on recordings from the former group. We will do this using a stimulus specific 

to HFs (ambient heating). Despite the common use of hormone replacement therapy, its effects 

on sleep have not been established. In Study 4, we will systematically manipulate ambient 

temperature during sleep in symptomatic women before and during estrogen replacement and in 

a placebo-control group. In Study 5, we will determine the effects of elevated sympathetic 

activation on HFs and sleep using a stimulus that does not, by itself, disrupt sleep (orthostasis). 

Grant: 5R03MH063932-02

Program Director: WINSKY, LOIS M.

Principal

Investigator: ECKEL, LISA A PHD 

Title: MECHANISM OF ESTROGEN'S INHIBITORY EFFECTS ON 

FEEDING 

Institution: FLORIDA STATE UNIVERSITY TALLAHASSEE, 

FLORIDA 

DESCRIPTION (provided by applicant): The ovarian cycle has profound effects on food intake 

in a variety of species, including humans. This effect is very prominent in female rats which 

display a 20 - 40 percent decrease in food intake during the estrous (sexually receptive) phase of 

the cycle. This decline in food intake during estrus appears to be mediated, at least in part, by 

increased sensitivity to the satiety effects of cholecystokinin (CCK), a gut peptide that is released 

during meals and functions to decrease food intake by generating a satiety signal that is relayed 

155 
 

to the brain via the vagus nerve. The importance of the rat's ovarian cycle in the control of food 

intake is revealed by ovariectomy, which increases food intake, decreases sensitivity to CCK, 

promotes body weight gain and, in the absence of estrogen replacement, induces obesity. 

Although the decline in estrogen activity appears to mediate the hyperphagia and associated 

body weight gain following ovariectomy, it is not known whether changes in endogenous 

estrogen activity mediate the decrease in food intake and increase in CCK satiation expressed 

during estrus in cycling rats. One goal of this proposal is to determine whether antagonism of 

central estrogen receptor activity will block the estrous-related decrease in food intake and 

increase in CCK satiation. To investigate this hypothesis, food intake and meal patterns will be

monitored in cycling rats treated with an antiestrogen at various phases of the estrous cycle. A 

second goal is to use c-Fos immunocytochemistry, a marker of neuronal activity, to determine 

whether increased sensitivity to the satiety effects of CCK during estrus is mediated by increased 

responsivity of neurons that process satiety signals generated by consumption of a meal and by 

injection of CCK. A third goal of this proposal is to determine the brain areas where endogenous 

estrogen acts to decrease food intake and increase CCK satiation during estrus. In this 

experiment, in situ hybridization and immunocytochemistry techniques will be combined to 

determine whether those neurons that are activated by CCK express estrogen receptors. 

Together, these studies have the potential to broaden our understanding of the mechanism by 

which food intake is controlled across the estrous cycle of female rats. Because eating disorders 

are more prevalent in women than in men, this proposal targets an important research question 

with clear clinical relevance . 

Grant: 5R03MH065460-02

Program Director: ANDERSON, KATHLEEN C.

Principal

Investigator: FRICK, KARYN M PHD 

Title: ESTROGENIC-CHOLINERGIC INTERACTIONS IN MEMORY

MODULATION

Institution: YALE UNIVERSITY NEW HAVEN,

CONNECTICUT

Project Period: 2002/12/01 - 2004/11/30 

No Abstract Available 

Grant: 5R01MH065990-02

Program Director: WINSKY, LOIS M.

Principal Investigator: COHEN, ROCHELLE S. PHD 

Title: ESTROGEN AND CAM KINASE IV IN THE LIMBIC SYSTEM

Institution: UNIVERSITY OF ILLINOIS AT CHICAGO CHICAGO, ILLINOIS

Project Period: 2003/09/30 - 2007/08/31 

DESCRIPTION (provided by applicant): Clinical studies have shown that estrogen (E2) can 

ameliorate symptoms of mood disorders in women, including severe depression. The presence of 

156 
 

symptoms may represent an abnormal response to normal hormonal changes, thereby implicating 

contextual factors in the brain in the etiology of these symptoms. Some of these factors include 

second messenger systems that lead to the production of neurotrophic agents, including brainderived neurotrophic factor (BDNF). Chronic stress results in deleterious effects on neurons and 

synapses which, in turn, may be related to alterations in affective behavior. Because of its 

involvement in cellular and synaptic growth and/or function, BDNF may counteract these 

negative effects and restore the appropriate behavioral responses. The gene transcription factor 

cyclic AMP response element-binding protein (CREB), has been shown to be a target of 

antidepressant and E2 action. Activation of CREB can lead to transcription of the BDNF gene. 

We propose that the Ca2+/calmodulin-dependent protein kinase IV (CaMK IV) pathway, 

"CaMK IV - CREB - phosphorylated CREB (pCREB) - BDNF," mediates some of the effects of 

long-term E2 treatment on behavior. Long-term E2 treatment results in the persistence of these 

messengers, even after two weeks. E2 may regulate CaMK IV and BDNF via alterations in their 

mRNAs; we will perform in situ hybridization to address the hypothesis that E2 regulates levels

of CaMK IV mRNA and BDNF mRNA. We will also determine if E2 decreases relevant

phosphatases, including protein phosphatase 2A and the calcineurin pathway, negative regulators 

of CaMK IV and pCREB, respectively. To determine if CaMK IV, CREB and/or BDNF mediate 

E2 effects in the forced swim test, a test for the efficacy of antidepressants in rodents, antisense 

oligodeoxynucleotides (ODNs) to CaMK IV, CREB or BDNF will be infused into the amygdala 

or hippocampus and animals will be subjected to the test conditions. Infusion of these antisense 

ODNs may interfere with the positive effects of E2 on forced swim. We will also determine if 

infusions of BDNF protein with the antisense ODNs to CaMK IV and CREB reverse the actions 

of the ODNs on behavior. These experiments will give insight to the molecular effects of E2 in 

areas of the brain related to affective processing and will uncover mechanisms that may allow 

hormonal intervention for the amelioration of female-related mood disorders. 

Grant: 5K23MH066978-02

Program Director: DOLAN-SEWELL, REGINA 

Principal

Investigator: JOFFE, HADINE MD 

Title: PHYSIOLOGY OF ESTROGEN'S MOOD EFFECT IN MENOPAUSAL 

WOMEN 

Institution: MASSACHUSETTS GENERAL HOSPITAL BOSTON,

MASSACHUSETTS

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Career Development 

Award focuses on developing expertise in the interdisciplinary field of perimenopausal 

depression. Menopause is universal in women, and depressive disorders occur in 10% of 

perimenopausal women. This project will dissect the mechanisms by which estrogen replacement 

therapy (ERT) treats depression in menopausal women. We hypothesize that ERT improves 

mood by a direct CNS effect, rather than by simply treating hot flushes and sleep disruption. A 

physiologic intervention study will compare the mood effect of ERT with that of a hypnotic 

agent in depressed perimenopausal women. The direct neuromodulatory effect of ERT on mood 

will be unmasked by controlling for ERT's effect on sleep. Polysomnographic (PSG) studies will 

be used to explore changes in sleep architecture that occur with ERT and the hypnotic agent 

zolpidem. This study will: (1) identify the elements critical to estrogen's antidepressant benefit; 

(2) characterize subpopulations of perimenopausal women whose depression can be treated with 

157 
 

non-hormonal therapies and those who require treatment with ERT; and (3) define optimal 

management of depression in perimenopausal women. Understanding the components of ERT's 

effect on mood will also advance the field of hot-flush research by examining the impact of hot 

flushes on sleep, mood, and quality-of-life. This is critical for the development of novel estrogen 

alternatives and putative hot-flush therapies increasingly used in women with breast cancer and 

others unable or unwilling to take ERT. ENVIRONMENT: The proposed study will be based at 

Massachusetts General Hospital (MGH), with outstanding interdisciplinary sponsorship and 

consultant input. PSG studies will be performed at McLean Hospital. I will receive mentorship 

from Lee Cohen, M.D., in the Department of Psychiatry, and Janet Hall, M.D., in the 

Reproductive Endocrinology Unit of the Department of Medicine at MGH. Both sponsors are 

internationally recognized in their respective fields and have exceptional track records as 

effective research mentors. Their combined expertise will shape my career development in this 

interdisciplinary field. CAREER DEVELOPMENT PLAN: Physiologic investigation of mood 

disturbance in menopausal women requires that I acquire knowledge of (1) sleep medicine; and 

(2) research methods for healthoutcomes assessment and clinical intervention studies using 

physiologic measures. I will receive formal training in each of these specific research areas under 

the supervision of expert consultants. Such training will lay the foundation for a career of clinical 

investigation into the physiology of perimenopausal depression and the impact of hot flushes on 

sleep, mood, and quality-of-life. 

Grant: 1R01MH067602-01A1

Program Director: BRADY, LINDA S.

Principal

Investigator: MELTZER, CAROLYN C. MD 

Title: AGE/SEX EFFECTS ON THE CENTRAL SEROTONIN 

SYSTEM

Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH, 

PENNSYLVANIA 

DESCRIPTION (provided by applicant): Advances in molecular biology and neuroimaging, 

coupled with the imperative caused by the aging of the population, have created fertile ground 

for improved understanding of the interaction between brain function and behavior. It is well 

recognized that the integrity of the central serotonin (5-HT) neurotransmitter system is essential 

for the proper regulation of mood, behavior, and memory. Selective age effects on the 5-HT 

system may impact risk and manifestations of depression across the lifespan and cognitive 

impairment in the elderly. Further, mood disorders and Alzheimer's disease affect a 

disproportionate number of women, yet the etiology and potential treatment implications of this 

gender association are understudied. Indeed, sex differences in the effect of age on the 5-HT 

system is of etiologic and therapeutic importance to potential gender influences on susceptibility, 

course, and treatment of mood and cognitive disturbances in normal aging and in association 

with neurodegenerative disease. The aim of this proposal is to define the role of aging and the 

potential influence of gender on serotonergic function. This study focuses on two complementary 

5-HT receptor subtypes, 5-HT1A and 5-HT2A, because of their association with depression and 

memory function and putative role in mechanisms of antidepressant treatment response; further, 

these receptor subtypes are pharmacologically well-characterized and amenable to in vivo study 

in humans with new highly selective ligands for positron emission tomography (PET). 

Quantitative image analysis will include a magnetic resonance (MR) imaging-based partial 

158 
 

volume correction developed by the PI in order to minimize the diluting effects of cerebral 

atrophy, a source of bias that frequently confounds PET studies of aging. The goal of this work is 

to provide unique and direct information on the effect of age and potential influence of sex on 

human serotonergic function. Thus, this revised R01 application complements our funded R01 

(MH59945), which uses PET and serotonergic ligands to investigate treatment response 

mechanisms in late-life depression. The current proposal further reinforces the strong 

commitment by the PI and colleagues to apply advanced quantitative in vivo imaging techniques 

to define neurobiologic correlates of aging and neuropsychiatric disorders of late life. 

Grant: 1R01MH069732-01A1

Program Director: COLPE, LISA J.

Principal

Investigator: HARLOW, BERNARD L PHD 

Title: RISK FOR NEW ONSET OF DEPRESSION IN PERIMENOPAUSAL 

WOMEN 

Institution: BRIGHAM AND WOMEN'S HOSPITAL BOSTON,

MASSACHUSETTS

DESCRIPTION (provided by applicant): Several epidemiological studies have shown that 

women, compared to men, are at a substantially greater risk of depression beginning in 

adolescence and continuing through their entire life. In addition, the age-specific incidence of 

depression in women peaks during the late reproductive years. However, the extent to which the 

perimenopause represents a time of greater risk for new onset of depression in women with no 

history of mood disorder is yet to be determined. The Harvard Study of Moods and Cycles 

(HSMC), a population-based prospective study of late premenopausal aged women, is uniquely 

suited to investigate this association because of the rigorous systematic assessment of psychiatric 

morbidity and menstrual cycle changes over time. In this study, approximately 1000 

premenopausal women with and without a lifetime history of depression were followed over 36 

months with semi-annual psychiatric assessments, medical history interviews, and early 

follicular phase blood specimens to measure reproductive hormones in serum. Our published 

results have shown that 1) age at menarche and other events in early reproductive life are 

associated with risk for depression, 2) women with a lifetime history of major depression 

(particularly those with more severe depressive symptoms proximate to the perimenopause) are 

at a greater risk of developing menstrual cycle changes consistent with those that signal an 

earlier transition to the perimenopause compared to women with no depression history, and 3) 

early follicular phase FSH and LH are higher, and estradiol levels are lower in depressed 

compared to non-depressed late reproductive aged women as they move toward the climacteric. 

Having carefully gathered prospective data on psychiatric disorders and changes in menstruation, 

we now have a unique opportunity to evaluate the impact of the perimenopausal transition on 

risk of first onset of mood disturbance. In this current submission, we plan to include 

approximately 500 women from the original HSMC with no lifetime history of major depression, 

and will enrich this sample with an additional 200 largely minority women from the general 

population. Our preliminary data suggest that an earlier onset to the perimenopausal transition is 

associated with a 3-fold risk of new onset of major depression in women with no prior history of 

depressive disorder. Furthermore, it appears that initiation of hormonal therapy to treat menstrual 

cycle changes, irregularities, or somatic symptoms attenuates this increased risk of a first onset 

of depressive episode. We plan to better assess the effect of onset to the perimenopause on the 

159 
 

risk for new onset of mood disturbance independent of past depression history that clearly 

influences the risk of recurrent episodes. The present project is designed to confirm and expand 

upon these preliminary findings by using structured clinical interviews for accurate psychiatric 

diagnoses, and comprehensive assessments of clinical symptoms at the time of the menopausal 

transition. 

Grant: 1R03MH069780-01

Program Director: WINSKY, LOIS M.

Principal

Investigator: AKAMA, KEITH T PHD 

Title: NON-GENOMIC ACTIONS OF ESTROGEN ON SYNAPSE 

FUNCTION.

Institution: ROCKEFELLER UNIVERSITY NEW YORK, NEW 

YORK 

DESCRIPTION (provided by applicant): In aging, decreased levels of circulating estrogen are 

associated with memory impairment and cognitive decline, but the molecular events underlying 

this dysfunction are poorly understood. Therefore, the broad, long-term goal is to understand 

how estrogen supports synaptic activity, with particular focus on the hippocampus, the area of 

the brain associated with learning and memory. The specific goal of this project is to define the 

molecular pathways by which estroqen regulates NR1, the obligate subunit of the NmethyI- Daspartate (NMDA) receptor (NMDAR). Mice lacking NR1 display an absence of hippocampal 

synaptic plasticity and have impaired spatial memory. In wild-type animals, endogenous 

increases in estrogen across the estrous cycle are associated with improved spatial memory, 

increased NR1 protein levels, and increased NMDAR binding in the hippocampus. Preliminary 

data indicate that estrogen also can directly increase NR1 mRNA levels in vitro, yet there are no 

estrogen receptor (ER) response elements in the genomic NR1 promoter. Therefore, the testable 

hypothesis is that estrogen stimulates NR1 activity and thus supports consequent synaptic 

function -- using non-genomic mechanisms on both promoter activation as well as post 

translational modification. The project has four independent yet inter-related aims: Aim 1 will 

quantify estrogen-stimulated increases in NR1 mRNA levels by using organotypic hippocampal 

slice cultures and quantitative RT-PCR to achieve significant sensitivity over current in vivo 

approaches. Aim 2 will quantify the non-genomic actions of estrogen on the NR1 promoter using 

NR1 reporter constructs and mutant variants. Aim 3 will determine how different ER isoforms

(ERalpha or ERbeta) lead to NR1 promoter modulation. Aim 4 will determine how non-genomic 

estrogen actions post-translationally phosphorylate NR1 to modify NMDAR localization, 

sensitivity, and activity at the synapse. The NMDAR is the major glutamatergic receptor in the 

hippocampus, and deficit in NR1 is associated with aging and human neurologic diseases. This 

project will elucidate how estrogen nongenomically stimulates and supports cognitive function 

by promoting synaptic activity in hippocampal neurons, and, by corollary, will explain one way 

the loss of estrogen may affect neuronal dysfunction observed in the aging process. 

Grant: 1R21MH069810-01A1

Program Director: WINSKY, LOIS M.

Principal Investigator: CALDWELL, JACK D MD 

Title: CHARACTERIZATION OF CENTRAL ABP/SHBG RECEPTORS

160 
 

Institution: UNIVERSITY OF ILLINOIS AT CHICAGO CHICAGO, ILLINOIS

DESCRIPTION (provided by applicant): An emerging model of action for steroid-binding 

proteins is that they are essential in delivering steroids to either steroid membrane or cytoplasmic 

receptors. Whereas the more commonly known model suggests that steroid-binding proteins such 

as sex hormone binding globulin (SHBG) are only made in the periphery and only deliver 

steroids to be passively released at the target cell, we have found that SHBG is produced in the 

brain where it facilitates female sexual receptivity. Therefore, we have two ends of the answer to 

the question of whether SHBG is a neuromodulator: its production and its behavioral effects. 

However, we need to find out whether and where there are receptors for SHBG in brain. In 

generating preliminary data, we have found that SHBG stimulates female sexual receptivity and 

that coupling it to dihydrotestosterone blocks this facilitative effect. We have found that 

microiontophoresing SHBG onto hypothalamic tissue sections results in an immediate 

depolarization of magnocellular neurons. We have found that cells transfected with either 

estradiol receptor alpha or beta respond to both SHBG and SHBG-estradiol application with an 

elevation of MAP kinase phosphorylation. Using SELDI-TOF mass spectrometry on affinity 

chromatography eluted hypothalamic tissue, we have identified protein peaks at 144000 and 

168000 daltons that seem to represent SHBG receptors. We have found SHBG produced in 

hypothalamic areas in the same neurons as the reproductively important peptide oxytocin. Both 

SHBG and oxytocin are found in varicosities and in synaptic vesicles suggesting they are 

released within the brain. Therefore, work done in several laboratories, collaborating together via 

the PI, has found that SHBG is made in brain, may be released in brain, [and] has important very 

rapid actions on neurons and cells in vitro, and so we would like funding to search for receptors 

for this potentially very important brain protein. This application proposes a confluence of 

particular scientific expertise including the PI and Drs. Gustav Jirikowski at the University of 

Jena, Germany, Jeffrey Tasker of Tulane University and Robert Shapiro at the Oregon Health 

Sciences University. In the words of one of the reviewers of the initial application, "The 

mechanism mediating the delivery of steroid hormones to their receptors has important 

implications for mental health, as well the action of steroid hormones in cancer, heart disease, 

and other disorders." This proposal examines this mechanism. 

Grant: 1R21MH070003-01A1

Program Director: WINSKY, LOIS M.

Principal

Investigator: ARNSTEN, AMY F.T. PHD 

Title: ESTROGEN, STRESS AND DYSFUNCTION OF PREFRONTAL 

CORTEX 

Institution: YALE UNIVERSITY NEW HAVEN,

CONNECTICUT

DESCRIPTION (provided by applicant): Depression and Post-Traumatic Stress Disorder 

(PTSD) are more prevalent in young women than men. Genetic studies link the CREB1 gene 

with recurrent depression in women but not men, supporting a neurobiological basis for this 

gender discrepancy. Both depression and PTSD involve dysfunction of the prefrontal cortex 

(PFC), a brain region that is 1) critical for regulating behavior, thought and affect, and 2) 

dysfunctional during exposure to uncontrollable stress. Stress is a major risk factor for 

depression, and life-threatening stress can cause PTSD. We hypothesize that estrogen promotes 

161 
 

sensitivity to stress, rendering women more susceptible to PFC dysfunction, and thus to stressrelated disorders. The proposed research will begin to identify the neurobiological mechanisms

through which estrogen exacerbates stress-induced PFC dysfunction. Research in male rats has 

shown that stress-induced PFC dysfunction arises from excessive catecholamine release in PFC, 

activating protein kinases A and C, which in turn phosphorylate CREB. Interestingly, alpha-1 

adrenoceptors (al R) drive this stress response, while alpha-2A adrenoceptors (a2AR) protect the 

PFC from stress, and estrogen is known to increase the expression of a1R and reduce the 

expression of a2AR. Our initial results show that cycling female rats with high levels of 

circulating estrogen are impaired by mild injection stress, by low doses of a pharmacological 

stressor, FG7142, and by brief periods of restraint stress which have no effect in males or 

females with low levels of estrogen. The proposed research will extend these studies to 

ovariectomized rats with and without estrogen replacement. Aim 1 will test the hypothesis that 

estrogen amplifies the cognitive and biochemical responses to restraint stress. Biochemical 

characterization will include measures of a1AR and a2AR expression, catecholamine turnover 

and phospho-CREB in PFC. Aim 2 will begin to explore the contribution of these biochemical 

changes to PFC cognitive function, testing whether the increased expression of a1R in the PFC 

of estrogen-treated rats renders them more sensitive to cognitive impairment. This research will 

begin to reveal how estrogen amplifies the neurochemical cascades that lead to activation of 

CREB and dysfunction of the PFC during stress 

Grant: 1F32MH070086-01A1

Program Director: DESMOND, NANCY L 

Principal Investigator: JASNOW, AARON M PHD 

Title: NEUROENDOCRINE MECHANISMS OF EMOTIONAL BEHAVIOR

Institution: ROCKEFELLER UNIVERSITY NEW YORK, NEW YORK

DESCRIPTION (provided by applicant): Natural fluctuations in estrogens have been associated 

with a number of affective disorders in humans. In particular, low levels of circulating estrogens 

are associated with increased symptoms of depression, anxiety and cognitive dysfunction, which 

can often be ameliorated with hormone replacement therapy. Little is known about the 

mechanisms or the sites of action through which estrogen is influencing emotion, however, they 

likely occur within the amygdala. Therefore, a comprehensive analysis of the effects of estrogen 

within the amygdala is needed to further our understanding of how this steroid hormone 

influences the development of neuropsychiatric disorders in humans. The goal of the current 

proposal is to (I) determine the genomic and neurochemical actions of estrogen within the 

amygdala and (II) how they influence fear and anxiety in female rodents. This will be

accomplished by examining estrogen-induced changes in gene expression within each region of 

the amygdala using quantitative-real-time-PCR (Q-PCR). These experiments will be followed by 

functional studies in which gene function knockdown with a novel antisense oligonucleotide 

moiety will be used to examine how estrogen-regulated genes influence fear and anxiety. These 

data will contribute to our knowledge of the hormonal mechanisms underlying fear and anxiety. 

Grant: 1F31MH071085-01A1

Program Director: DESMOND, NANCY L 

Principal

Investigator: COFER SMITH, CAROLINE D

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BS 

Title ESTROGEN MODULATES HIPPOCAMPAL MORPHOLOGY AND 

PLASTICITY 

Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM,

ALABAMA 

DESCRIPTION (provided by applicant): Estradiol (E2) has a role in learning and memory in 

mammals such as humans, primates and rats. Following the loss of E2, as occurs during aging, 

the hippocampus, a brain region important for cognition, undergoes alterations in morphology 

and synaptic transmission. Specifically, CA1 pyramidal cell dendritic spine density and the 

magnitude of long-term potentiation (LTP) decrease when the levels of E2 decline. I have shown 

that E2 transiently increases both spine density and LTP magnitude, with LTP returning to 

control levels prior to spine density. Whether a relationship exists between these two phenomena 

has not been determined but I have shown that blocking the estrogen-induced increase in spine 

density blocks the increase in LTP, which suggests these two phenomena are related. The goal of 

this study is to determine whether the increase in spine density is required for the increase in 

LTP magnitude, and if spines are necessary, whether the increase in LTP is due to an increase in 

NMDAR-only spines, termed silent synapses. Elucidating the contribution of E2 to morphology 

and synaptic plasticity in hippocampus will provide insight into the mechanism by which E2 

regulates cognition with age. 

163 
 

164 
 

National Institute of Neurological 

Disorders 

and Stroke 

(NINDS) 

165 
 

166 

National Institute of Neurological Disorders and Stroke 

Menopause-Related Research 

FY2004 

Molecular Mechanisms of Estrogen Neuroprotection (Wang, K08 NS41342) 

Female rats show less brain injury than male rats after an experimentally-induced stroke. 

However, removing the ovaries from female rats eliminates the protection from stroke-related 

brain injury, suggesting that female reproductive hormones, such as estrogen, might be 

neuroprotective. This study focuses on the molecular mechanisms that may contribute to this 

protective effect. 

Hormone Replacement Therapy and Ischemic Stroke Severity (Bushnell, K23NS41929-03) 

Animal studies have shown that estrogen reduces stroke severity, but the impact of hormone 

replacement therapy (HRT) on stroke severity in humans is not known. This observational study 

seeks to determine if there are differences in stroke severity and outcome based on whether a 

woman uses HRT or not. To study this question, researchers will record the stroke severity of 

women admitted to the hospital with acute ischemic stroke, measure differences in markers of 

the blood coagulation system, and follow the women after the stroke to determine functional and 

quality of life outcomes. The investigators will then assess whether a prior history of HRT use is 

correlated with the severity of the initial stroke or with the outcomes after the stroke. 

Pharmacologic Plasticity in the Presence of Pain (subproject-Sex Differences and Estrogen 

Dependency of Spinal Cord Analgesia) (Eisenach/Tobin, P01NS41386) Studies have noted sex 

differences in analgesic responses to certain painkillers, which may result from higher levels of 

spinal neuron activity in response to these drugs in females. This group of studies in animals and 

humans will further examine the neural circuitry involved in chronic pain, and will investigate 

whether the sex difference in the female response to certain painkillers is dependent on hormones 

such as estrogen. The overall objective of this project is to better understand chronic pain and to 

develop improved treatment options. 

Epidemiology and Genetics of Parkinson’s Disease (Rocca, R01NS33978) 

Men are more likely to develop Parkinson’s disease (PD) than pre-menopausal women, but the 

reasons for this sex difference are not fully understood. Hormones such as estrogen could be one 

factor, since the likelihood of developing Parkinson’s disease increases for women after 

menopause. In addition, postmenopausal women with PD improve with estrogen replacement 

therapy. These observations suggest that estrogen might influence the survival of the dopaminecontaining neurons that degenerate in PD. In this study, the investigators will sample 800 

Parkinson’s disease (PD) patients and 800 PD-free control subjects. Study participants will be 

asked about tobacco, coffee and alcohol use. Women will be assessed for estrogen replacement 

therapy after menopause and other reproductive and estrogen-related factors. The case-control 

study may confirm preliminary findings on the role of estrogen in PD. 

Gender Differences in Cardiac Arrest/CPR (Traystman, R01NS46072) 

Despite four decades of research on cardiac arrest and CPR, clinical outcome remains poor. 

Neurologic and neuropsychologic evaluations of potential differences between men and women 

after cardiac arrest have not been examined closely. Preliminary findings indicate that brains of 

females are better protected from cardiac arrest/CPR than males, and that estrogen may be 
 

167 

involved with this neuroprotection. This study will contribute to our understanding of the role of 

estrogen in neuroprotection, and as a possible therapy for patients of either sex. 

Estrogen Modulation of Brain: A-beta Metabolism in vivo (Gandy, R01NS41017) 

Evidence suggests that estrogen replacement therapy in postmenopausal women appears to 

reduce the risk of Alzheimer’s disease (AD), or delay its onset. However, the mechanism by 

which estrogen exerts this neuroprotective role is unclear. The investigators will examine the 

role of estrogen on the release of certain peptides (A-beta) that are aggregated in the brains of 

individuals with AD. Guinea pigs, transgenic mice and cell cultures will be used to test the 

effects of estrogen-like drugs on the regulation and metabolism of the A-beta protein. 

Ovarian steroid hormones and hippocampal plasticity (Levy, R01NS41582) Estradiol alters 

the activity of certain neural connections in the brain’s hippocampal region. This synaptic 

plasticity may result in enhanced memory. Estradiol also increases the excitability of neurons in 

the hippocampus, and may cause changes in synaptic plasticity in this brain region. Using 

appropriate testing methods in rats, the investigators will measure the effect of estradiol on the 

excitability of hippocampal neurons, and ascertain whether synaptic plasticity is increased over 

time. This study will provide important insights for understanding the biological basis for 

memory problems that can occur with menopause. 

Estrogen, BDNF and hippocampal hyperexcitability (Scharfman R01NS037562) 

The central hypothesis of this proposal is that estrogen induces the expression of brain derived 

neurotrophic factor (BDNF) in the brain’s hippocampus, and this leads to changes in neuronal 

excitability that ultimately increase the susceptibility to seizures. This hypothesis is relevant to 

women with epilepsy, including those with catamenial epilepsy, or those taking estrogen. 

Experiments to measure neuronal excitability will be conducted using rats at various stages of 

the estrus cycle, and using ovariectomized rats with and without hormone replacement. 

Neuromodulation of reproduction during aging (Gerhold F31NS047875) 

The brain plays a critical role in the aging of the reproductive system. A small region of the 

brain’s hypothalamus is essential in providing time-of-day information needed to maintain 

normal surges of reproductive hormones, including gonadotropin releasing hormone (GnRH) and 

leutinizing hormone (LH). This study will investigate the neuronal activity that controls 

hormonal surges of GnRH and LH, and assess the effects of age on these processes. This 

research will enhance our understanding of factors that influence the menopausal transition. 

Estrogen: neuroprotection and rescue (Zukin, R01NS045693) 

Estrogen appears to protect neurons against damage caused by lack of oxygen, or ischemia, as 

can occur during a heart attack or stroke. Studies in animals have suggested that long-term 

treatment with estrogen can improve the survival rates of neurons exposed to ischemic 

conditions. The objective of this basic study is to identify the ways in which estrogen acts to 

protect neurons from damage in an animal model of ischemia. 

Hormones and biomarkers predicting stroke in women (Wassertheil-Smoller R01NS042618) 

The Women's Health Initiative clinical trial of estrogen plus progestin for the prevention of 

cardiovascular disease in healthy, postmenopausal women found increased risk of stroke in users 

of estrogen plus progestin. This study will investigate possible reasons for the increased risk of 

stroke by studying biomarkers of blood clot formation and inflammation. This population based 
 

168 

nested case-control study will compare biomarkers in 1050 ischemic stroke cases and 1050 

matched controls, drawn from the participants in the Observational Study component of the 

Women's Health Initiative (WHI-OS). 

Pathophysiology of HIV dementia in women (Wojna S11NS046278) 

The population of women with AIDS is increasing as a consequence of changes in the 

epidemiology of HIV infection. HIV associated dementia (HAD) continues to be one of the 

major complications of AIDS and little is known about hormonal modifiers, which can impact on 

the development and severity of HAD in women. This cross sectional study will identify HIV 

infected women at high risk of developing HAD and will determine if gonadal dysfuction and 

oxidative stress contribute to the dementia. 

Beta endorphin neurons and the control of homeostasis (Kelly R01NS038809) 

Estrogen influences homeostatic functions like temperature regulation, stress responses, feeding, 

motivation and reward. Selective estrogen receptor modulators (SERMs) that produce the 

beneficial effects of estrogen in the central nervous system but lack the adverse effects of 

traditional hormone replacement therapy are greatly needed. These studies will not only identify 

the pathway(s) critical for rapid estrogen signaling in beta endorphin neurons but also may allow 

the development of new SERMs specifically targeting critical brain circuits involved in the 

control of homeostasis in the female. 

Neural control of temperature regulation (Boulant R01NS014644) 

Networks of neurons in the brain’s hypothalamus regulate body temperature and fever. Neurons 

in this region integrate information from the external and internal environment to generate 

changes in skin blood flow, sweating, and shivering. It is likely that this network is also affected 

by reproductive hormones, causing menopausal hot flashes and changes in body temperature 

during the menstrual cycle. This study will characterize these neurons and investigate how they 

form a connected network to control thermoregulatory responses. 

In vitro studies of steroid receptors in NF1 (Fishbein F30NS043951) 

Neurofibromatosis type I (NF1) is characterized by abnormal proliferation of cells in tumors 

known as neurofibromas. Neurofibromas are often aggravated during puberty and pregnancy, 

suggesting an altered sensitivity to steroid hormones. These studies will characterize the role of 

hormones in neurofibroma development, allowing patients with NF1 and their physicians to 

make more educated medical decisions about hormone therapies for birth control, menopause, or 

disease treatments. 

Study of tumor growth and cyst development in von Hippel Lindau disease (NINDS 

Intramural program, Protocol Number: 00-N-0140)

Patients with von Hippel-Lindau (VHL) disease develop cysts or tumors of the cerebellum, 

brainstem and spinal cord, as well as in other areas of the body. This study seeks to identify 

factors that predict or influence tumor progression or cyst development in order to better inform 

treatment decisions. Information will be prospectively collected about processes that may 

influence tumor progression in women, such as puberty, menopause, pregnancy, and effects of 

hormone therapy. 

Sex and gene expression conference (Sandberg R13NS048416) 
 

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This grant provided partial funding support for the fifth annual Sex and Gene Expression 

Conference (SAGE V), held March 18- 21, 2004. The primary goal of this conference was to 

explore the interaction between biological sex and genetic expression throughout the lifespan. 

The conference session topics included sexual dimorphism in the brain, the biology of aging, and 

gonad development, physiology and disease. 
 

170 
 

National Institute 

of Nursing 

Research 

(NINR)

171 
 

172 

National Institute of Nursing Research 

2004 Menopause Related Grants 

Grant Number Title Principle Investigator Institution 

2P30NR005051-06 Hormone Replacement Therapy Among 

Women with Disabilities Becker, Heather University of Texas Austin 

1R15NR008003-01A2 Nursing Interventions for Symptoms of 

Perimenopause Berg, Judith University of Arizona 

5R01NR007738-02 Home vs. Center-Based Weight Loss and 

Exercise in Menopause Dennis, Karen University of Central Florida 

5R01NRNR005339-05Estrogen/Platelet Interaction in Cerebral 

Ischemia Kearney, Marguerite Johns Hopkins University 

5R01NR004141-09 Menopausal Transition: A Biobehavioral 

Model of Symptoms Mitchell, Ellen University of Washington 

5R01NR005281-04 Heart Disease in Women: Estrogen 

Effects on Hemodynamics Sherwood, Andrew Duke University 

2U01NR004061-10A1 The Study of Women’s Health Across the 

Nation-Michigan Sowers, MaryFran University of Michigan at Ann 

Arbor 

5R01NR004861-04 Promoting Healthy Eating and Activity in 

Rural Women Walker, Susan University of Nebraska Medical Center 

5R01NR007743-03 Prevention of Osteoporosis in Breast 

Cancer Survivors Waltman, Nancy University of Nebraska Medical 

Center 
 

173 

National Institute of Nursing Research 

Menopause Related Grants 

FY 2004

Summary of Current NINR Grants Relevant to Menopause 

Hormone Replacement Therapy (HRT) among Women with Disabilities (Becker-NR005051). 

This study compares factors that women with physical disabilities consider when addressing decisions 

about HRT and aspects of decision making. Findings to date show that many women with disabilities do 

not know about HRT effects, and would like more tailored information. Provider recommendation and 

willingness to comply with that recommendation were the strongest predictors of HRT use for this 

population. Findings from this research will add to the limited but growing body of knowledge regarding 

the menopausal health needs of disabled women. 

Nursing Interventions for Symptoms of Perimenopause (Berg-NR008003). 

Increasingly, women are choosing alternatives to hormone replacement therapy (HRT) for symptom 

management during the perimenopausal transition, although effectiveness of these alternatives have not 

been well studied. NINR funded researchers employing a longitudinal repeated measures randomized 

three-group design: (a) multimodal treatment package (high fiber, low-fat diet; moderate exercise; stress 

reducing techniques), (b) soy isoflavone capsules, and, (c) a control condition - are investigating their 

effectiveness at managing severe perimenopausal symptoms. The information gleaned from this pilot 

study will inform a larger intervention trial. 

Home vs. Center Based Weight Loss and Exercise in Menopause (Dennis-NR007738). 

Evidence suggests that multi-faceted obesity treatment promotes the best weight loss outcomes, however 

the most effective site and methods for treatment delivery and follow-up care remain unknown. The 

researchers will test the efficacy of a HOME vs. CENTER-based diet and exercise intervention for 

postmenopausal women. Findings may help to identify best practice care for obese, sedentary, and 

postmenopausal women. 

Estrogen/Platelet Interaction in Cerebral Ischemia (Kearney-NR005339).

Research shows that premenopausal women are at a lower risk for CVD when compared with men. 

Researchers are clarifying the role of exogenous estrogen therapy in ischemic brain injury both 

mechanistically and according to dosage. Findings may help to clarify the role of estrogen as a potential 

therapy for both genders. 

Menopausal Transition: A Biobehavioral Model of Symptoms (Mitchell-NR004141). 

Although information related to the science of menopause is accruing, little remains known about the 

natural history of the menopausal transition, particularly the years prior to menopause. NINR funded 

researchers are continuing to build on their longitudinal description of the early, middle and late stage of 

the menopausal transition in a group of midlife women. Measures include hormone changes, perceived 

stress, physiologic stress arousal, symptoms, and depressed mood during three stages of the menopausal 

transition. Additionally, the study will investigate the effects of genetic polymorphisms of the estrogen 

receptor gene and estrogen metabolic genes on estradiol and estrone levels, age of onset of middle and 

late transition and menopause, and menstrual bleeding. 

Heart Disease in Women: Estrogen Effects on Hemodynamics (Sherwood-NR05281). 

Coronary heart disease (CHD), the leading cause of death in women in the U. S., increases rapidly 

following menopause when estrogen levels decline. Researchers are examining the acute effects of 

estrogen and estrogen/progesterone on vascular endothelial function and on peripheral vascular resistance 
 

174 

in postmenopausal women with a history of CHD. Information derived for this study could enhance our 

understanding of how HRT may alter risk in CHD. 

The Study of Women’s Health Across the Nation (SWAN) (Sowers-NR004061). 

Funded in September 1994 by NINR and NIA, with support from the ORWH, OBSSR, NICHD, NIMH, 

NCMHD, and NCCAM, SWAN is a multidisciplinary epidemiological study of the natural history of 

menopause, designed to characterize menopause in terms of ovarian aging, risk factors symptoms, 

cardiovascular risk, and bone health in an ethnically diverse sample (African- Americans, Caucasians, 

Chinese, Hispanics, and Japanese). NINR funds the clinical site at the University of Michigan where the 

investigator is examining menopausal related changes in a sample of more than 320 African-American 

and 220 Caucasian women age 40-55. Women are being followed longitudinally for changes in such 

variables as joint health, bone density and body composition. This is one of the first epidemiological 

studies to examine the menopausal effects in perimenopausal women of 5 ethnic groups. 

Promoting Healthy Eating and Activity in Rural Women (Walker-NR004861). 

Although women’s health risks increase at menopause, chronic diseases, associated disabilities and 

increased economic costs are not unavoidable consequence of aging. Employing a longitudinal 

randomized control trial, NINR funded researchers are investigating the impact of an 

individualized/tailored intervention based upon a Health Promotion Model (HPM) to a standard non 

individualized intervention focused on the initiation and maintenance of physical activity and health 

eating habits. Outcomes include both behavioral measures and biological markers and findings have the 

potential to make a substantial contribution to the literature on the initiation and maintenance of health 

lifestyle behaviors. 

Prevention of Osteoporosis in Breast Cancer Survivors (Waltman-NR007743). 

A substantial percentage of women with breast cancer have estrogen receptor positive tumor status and 

are therefore ineligible for hormone replacement therapy. These women are particularly vulnerable to 

osteoporosis since without estrogen, bone loss occurs rapidly the first five years of menopause onset and 

continues over time, albeit at a slower rate. NINR funded researchers are investigating whether 

strength/weight training exercises enhance the effectiveness of risedronate (5 mg/day), calcium (1200 

mg/day), and vitamin D (400 IU/day) in improving bone mineral density (BMD) in post-menopausal 

breast cancer survivors. Findings from this study have the potential to provide evidence of an effective 

alternative to HRT for treatment of osteoporosis in breast cancer survivors who ineligible for HRT. 

Summary of Published NINR Findings Relevant to Menopause 

Dormire SL, Reame NK. (2003). Menopausal hot flash frequency changes in response to experimental 

manipulation of blood glucose. Nursing Research, 52 (5): 338-343. 

Primary Question: Is there a significant difference in the incidence of menopausal hot flashes between 

conditions of fasting and experimentally sustained blood glucose concentrations? 

Summary of Findings: Hot flashes are a frequently reported symptom of menopause, generally associated 

with declining estrogen levels. Postmenopausal women on hormone replacement therapy were asked to 

stop their medication and maintain a diary of hot flash frequency. When frequency was at least 4 times 

per day, the women were admitted to a research center, and their blood glucose levels were manipulated 

by IV infusions. There was a significant reduction in hot flashes when the women had elevated blood 

glucose levels similar to those found after a meal. Fasting may trigger the mechanism for menopausal hot 

flashes. 

Sternfeld B, Wang H, Quesenberry Jr. CP, Abrams B, Everson-Rose SA, Greendale GA, Matthews KA, 

Torrens JI, & Sowers M. (2004). Physical activity and changes in weight and waist circumference in 
 

midlife women: findings from the Study of Women’s Health Across the Nation. American Journal of 

Epidemiology, 160 (9): 912-922. 

Primary Question: Are changes in body weight and fat deposition in midlife women related to

menopause, or are they consequence of the normal aging process? 

Summary of Findings: Using data from the Study of Women’s Health Across the Nation (SWAN), 

researchers analyzed the patterns of change in weight, waist circumference, activity level, and exercise for

over 3,000 premenopausal or early perimenopausal women. Over the 3-year study period, the averages 

for both body weight and waist circumference increased by 3%. There were no differences in weight gain 

or waist circumference related to menopause status. However, women who participated in sports or 

exercise or increased their daily routine activities demonstrated a slower gain or even a decrease in 

weight. Physical activity, both through specific exercise and as part of an active lifestyle, can help midlife 

women maintain a healthy weight. 

Berman DM, Nicklas BJ, Ryan AL, Rogus EM, Dennis KE, Goldberg AP. (2004). Regulation of lipolysis 

and lipoprotein lipase after weight loss in obese, posmenopausal women. Obesity Research, 12 (1): 32-39. 

Primary Question: Will a low calorie and a low-intensity walking exercise program affect the regulation 

of lipolysis in obese, postmenopausal women? 

Summary of Findings: The metabolic effects of a low calorie and exercise program were measured for 

obese, post-menapausal women in relation of a low calorie diet and low-intensity exercise. 

Responsiveness to basal lipolysis was greater in abdominal fat cells than in gluteal fat cells, but there 

were no differences in postreceptor-stimulated lipolysis, plasma triglycerides, or HDL-C levels. Weight 

loss in these women does not affect regional fat metabolism and may predispose them to develop 

abdominal fat. 

Sowers M, Derby C, Jannausch ML, Torrens JI, Pasternak R. (2003). Insulin resistance, hemostatic 

factors, and hormone interactions in pre-and perimenopausal women: SWAN. The Journal of Clinical 

Endocrinology & Metabolism. 88 (10): 4904-4910. 

Primary Question: Are reproductive hormones in women, including FSH, estradiol, and testosterone, 

associated with clotting factors and insulin resistance?

Summary of Findings: The role that female reproductive hormones play on reducing the incidence of 

heart disease in women by minimizing thrombosis remains unclear, but insulin resistance may be one 

contributing factor. As part of the Study of Women’s Health Across the Nation (SWAN), hormone 

concentrations, clotting factors, and insulin and glucose levels were measured for over 3,000 midlife 

women. As expected, pre- and perimenopausal women with diabetes had higher insulin values and insulin 

resistance, a higher body mass index, and elevated clotting factors, compared to women without diabetes. 

Sex hormone binding globulin (SHBG) was inversely associated with insulin resistance, and dampened 

the relationship between clotting factors and insulin resistance. 

Santoro N, Lasley B, McConnell D, Allsworth J, Crawford S, Gold EB, Finkelstein JS, Greendale GA, 

Kelsey J, Korenman S, Luborsky JL, Matthews K, Midgley R, Powell L, Sabatine J, Schocken M, Sowers 

MF, Weiss G. (2004). Body size and ethnicity are associated with menstrual cycle alterations in women in 

the early menopausal transition: The Study of Women’s Health across the Nation (SWAN) Daily

Hormone Study. The Journal of Clinical Endocrinology & Metabolism. 86 (6): 2622-2631. 

Primary Question: What are the baseline biological and demographic characteristics and daily hormonal 

patterns of the menstrual cycles of midlife women from different ethnic groups in the United States? 

Summary of Findings: The Daily Hormonal Study was a subset of the Study of Women’s Health Across 

the Nation (SWAN) involving over 800 women who collected first-void urines daily for one complete 

menstrual cycle, or for 50 days in the absence of menstruation. Over 80% of the cycle specimens showed 

evidence of luteal activity indicating continued hormone production. Women who were 49 years of age or 

older were had more irregular cycles and less luteal activity, while women with a lower body mass index 

175 
 

had shorter cycles and higher hormone levels. Chinese- and Japanese-American women had lower 

estrogen excretions. Smoking did not affect cycle length or hormone concentrations. The findings suggest 

that the ovary remains sensitive to elevated follicle stimulating hormone in the early menopause 

transition. 

Sampselle CM, Harris V, Harlow SD, Sowers M. (2002). Midlife development and menopause in African 

American and Caucasian women. Health Care for Women International, 23: 351-363. 

Primary question: What are the meanings that midlife women attach to the menopause transition, and do 

these differ between White and Black women?

Summary of findings: For midlife women, mental health care assessments have often focused on issues 

relating to the menopause transition, ignoring broader developmental and lifestyle changes. From focus 

group discussions with midlife women, most identified major life milestones relating to child bearing and 

rearing, mortality, changing family relationships, increasing self-efficacy, and life experiences, while few 

mentioned menopause. Many women felt that their turn had come to pursue their own interests. Black 

women tended to note menopause as a normal phase of life, while White women focused more on the 

signs of aging. Those past menopause often expressed relief at the freedom it brought. 

Sampselle CM, Harlow SD, Skurnick J, Brubaker L, Bondarenko I. (2002). Urinary incontinence 

predictors and life impact in ethnically diverse perimenopausal women. Obstetrics & Gynecology, 100 

(6): 1230-38. 

Primary question: What is the prevalence, associated risk, and the daily impact of mild to severe urinary 

incontinence among perimenopausal women? 

Summary of findings: While urinary incontinence (UI) is estimated to affect one third of older women in 

the US, little is known about its cause, range of severity, or difference in prevalence among different 

ethnic groups. Using survey data from the Study of Women’s Health Across the Nation (SWAN), 

researchers found that over half of perimenopausal women had experienced UI, with one-quarter 

reporting moderate to severe leakage. White women experienced the highest incidence, and Hispanic 

women the lowest. Associated risk factors included parity, perimenopausal status, diabetes, obesity, and 

current smoking. The high incidence of UI warrants screening among midlife women. 

Glazer G, Zeller R, Delumba L, Kalinyak C, Hobfoll S, Winchel, J, Hartman P. (2002). The Ohio Midlife 

Women’s Study. Health Care for Women International, 23: 612-630. 

Primary question: How do menopause symptoms and menopause status, attitudes, coping, and 

demographic characteristics affect health-promoting activities for White and Black women in the United 

States?

Summary of findings: The Ohio Midlife Women’s Study followed both pre- and post-menopausal women 

around the time of the menopause transition. Results found that roughly one third showed signs of 

anxiety, and one quarter suffered from depression, with the highest levels occurring around the onset of 

menopause. However, menopause status itself was not related to anxiety or depression. Common 

menopause symptoms included loss of energy, irritability, tension, headaches and joint pain, and trouble 

sleeping. Higher educational levels, more effective coping, and a more positive attitude towards 

menopause helped to enhance health promoting behaviors such as exercise, nutrition awareness, and selfactualization. Stress was more strongly related to health outcomes and behaviors than menopause status. 

Villarruel AM, Harlow SD, Lopez M, Sowers MF. (2002). El cambio de vida: conceptualizations of 

menopause and midlife among urban Latina women. Research and Theory for Nursing Practice: An 

International Journal, 16 (2): 91-102. 

Primary question: What are the experiences of Latina women in the United States?

Summary of findings: Menopause, a vital life-cycle phase for women, is imbued with many personal, 

social, and cultural meanings. In focus group interviews, older Latina women discussed the role that 

176 
 

menopause played in their lives. Three common themes emerged: 1) menopause can reorder the harmony

and balance in life, 2) the “change of life” is a normal adult phase that women must pass through, and 3) 

this period is a time for women to reorient their lives to focus more on personal needs and desires. 

However, many women lacked basic knowledge about the course of menopause and possible ways to 

manage symptoms. In general, the women described menopause as a social and cultural phenomenon 

bringing an important change in their life, but many also expressed a need for more information.

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National Center 

for Complementary 

and Alternative 

Medicine 

(NCCAM) 

179 
 

NCCAM NIH Research and Other Efforts Related to Menopausal Transtition 

The mission of the National Center for Complementary and Alternative Medicine (NCCAM) is 

to explore complementary and alternative healing practices in the context of rigorous science; to 

train CAM researchers; and to disseminate authoritative information to the public and 

professionals. The list of CAM practices and therapies will change as some are proven to be safe 

and effective and become accepted as "mainstream" health care practices. NCCAM groups 

CAM practices within five major domains: (1) whole medical systems (i.e., traditional Chinese 

medicine, naturopathic medicine, Ayurveda); (2) mind-body medicine (i.e., meditation, 

biofeedback); (3) biologically based practices (i.e., herbal therapies, special diets); (4) 

manipulative and body-based practices (i.e., chiropractic, massage); and (5) energy medicine 

(i.e., reiki, qi gong). NCCAM conducts and supports basic and applied (clinical) research and 

research training within these five areas. 

NCCAM has a strong interest in menopausal health because of the number of CAM modalities 

being used by peri- and post-menopausal women to treat a range of symptoms. In the wake of 

the Women’s Health Initiative, aggressive marketing campaigns are encouraging use of CAM 

products for menopausal symptoms, and the level of use is likely to increase. According to 

longitudinal survey data from the Study of Women’s Health Across the Nation (SWAN), almost 

50% of peri- and post-menopausal women had used CAM therapies in the past year. NCCAM 

continues to provide support for SWAN to continue data collection related to CAM use and the 

menopausal transition. 

NCCAM has taken a multi-pronged approach to improving our knowledge of CAM for the 

treatment of menopausal symptoms, convening workshops, producing reports, and supporting 

research and research training. For example, in January 2004, NCCAM, in collaboration with 

ORWH and several other NIH Institutes and Centers (ICs), convened a workshop to assess the 

quality of measures of hot flashes. (A summary of that workshop is available on the NCCAM 

website at http://nccam.nih.gov/health/hotflashes/hotflash_summ.htm) Critical to the evaluation 

of treatment efficacy is the quality of outcome measures. However, when objective measures 

(i.e., sternal skin conductance) are compared with self-reported measures taken under ambulatory 

conditions, women significantly under-report the frequency of hot flashes. In September 2004, 

NCCAM, along with NIA, NIBIB, and ORWH, issued an RFA for SBIR applications to improve 

sternal skin conductance technologies to facilitate long-term data collection on hot flash 

frequency under ambulatory conditions. We expect to make approximately five awards in FY 

05. 

NCCAM will also join NIA in sponsoring a state-of-the-science conference on the management

of menopause related symptoms, which will be convened in March 2005. This meeting will 

assess a range of therapies used to treat menopausal symptoms, including CAM modalities. 

In response to concerns raised about the safety of black cohosh, an herbal dietary supplement 

used to treat menopausal symptoms, NCCAM and the Office of Dietary Supplements convened a 

workshop in November 2004. NCCAM and other ICs participating in the workshop support 

clinical research on black cohosh. First and foremost is our concern for the safety of research 

subjects. Given ambiguity and uncertainty in the scientific literature, we wondered what 

additional actions if any NIH needed to take to protect participants in research. That workshop 

reviewed what is known about purported estrogenic activity of black cohosh, its effect on breast 

180 
 

181 

and prostate tissue, data from a murine model suggesting an increased incidence of metastatic 

lesions from breast to lung among animals fed black cohosh, and several cases of hepatotoxicity 

alleged to be connected to use of this dietary supplement. When the workshop report is 

completed, it will be available on the NCCAM website at http://nccam.nih.gov/. 

NCCAM supports a range of research projects on menopause, through individual grants and 

centers. Some of this research will provide much-needed information on the safety and efficacy 

of a number of CAM therapies used for menopausal symptoms while more basic research will 

provide valuable information on active ingredients, mechanisms of action, and the like. For 

example, ongoing basic research is looking at the effect of black cohosh extract on human breast 

tissue and the role of Cimicifuga racemosa as a serotonin modulator. A recently funded study is 

using molecular biology techniques to identify herbs that exhibit selective estrogenic activity for 

estrogen receptor beta, which appears to inhibit proliferation and breast tumor formation in 

mouse xenografts and thus presents a potentially safer treatment for menopausal symptoms than 

estrogen. And another recently funded study will collect plant specimens used for menopausal 

symptoms by indigenous populations in Guatemala and Costa Rica, make extracts from those 

plants, elucidate active constituents, and conduct bioassays to assess estrogenic and serotonergic 

activity and antioxidant effects. A new research training grant will look at the mechanisms by 

which black cohosh and red clover affect neurocognitive function and mood, using magnetic 

resonance imaging, diffusion tensor imaging, and other cutting-edge methodologies. 

Ongoing clinical research on menopause targets several CAM botanical therapies, including 

black cohosh, red clover, soy and other phytoestrogens, as well as the use of non-botanical 

treatments (e.g., therapeutic touch, macrobiotic diet) to deal with a range of symptoms, such as 

hot flashes, osteoporosis, and cognitive and affective problems. Examples of more clinically 

oriented research include a study on the impact of phytoestrogens on cognition, affect, and 

atherosclerosis and an epidemiologic study of the influence of soy consumption on menopause in 

Japan. The Center on Botanical Dietary Supplements for Women's Health in Chicago, supported 

by the Office of Dietary Supplements (ODS) and NCCAM, is completing studies on the clinical 

safety and efficacy of botanicals used to treat women's health with particular emphasis on 

therapies for menopause. Projects are preparing standardized dietary supplements, isolating 

active compounds for structure elucidation, and determining the mechanism of action and 

efficacy of several botanicals (i.e., black cohosh and red clover) used for menopausal symptoms, 

including hot flashes, bone turnover, and vaginal dryness. Work at another ODS/NCCAMfunded Center, the Botanical Center for Age-Related Diseases in Indiana, focuses on 

characterizing active ingredients in botanicals. The emphasis there is on determining the efficacy 

of polyphenolic compounds in reducing risk of age-related diseases including osteoporosis, 

cancer, cardiovascular disease, and neurodegeneration. Specific projects will study isoflavones 

and bone resorption in postmenopausal women, the effects of soy isoflavones on prostate, breast 

and bone, and soy and estrogen interactions on breast and endometrium markers. 
 

182 
 

National Center 

for Research 

Resources 

(NCRR) 

183 
 

National Center for Research Resources 

Menopause Related Research 

The National Center for Research Resources (NCRR) develops and supports critical research 

technologies that underpin health-related research to maintain and improve the health of our 

Nation's citizens. NCRR supports shared resources, sophisticated instrumentation and 

technology, animal models for study of human disease, clinical research, and research capacity 

building for underrepresented groups. 

Through its support of multidisciplinary research, NCRR is uniquely positioned to provide either 

primary research support or provide resource support in partnership with other Institutes or 

Centers to address emerging clinical and basic research needs, such as the study of menopause. 

Expansion of NCRR's present efforts in new biotechnologies and instrumentation, development 

of animal models, and clinical research will foster interdisciplinary collaborations and advance 

NIH's efforts to study menopause, as evidenced by the examples of on-going research that is 

cited below. 

Selective Estrogen Receptor Modulators improve cardiovasuclar function in menopause-induced 

rat model

During menopause, women have a higher propensity for developing cardiovascular disease. 

Studies have shown that treatment with selective estrogen receptor modulators (SERMS) 

improves cardiovasuclar status in menopausal women. The mechanisms involved, however, 

have not been elucidated. Researchers at the University of Puerto Rico Medical Sciences 

campus, with funding from the NCRR Research Centers in Minority Institutions (RCMI) 

Program, evaluated the effect of toremifene, a new member of the SERM family, on the 

cardiovascular status of an ovariectomized rat model. In these experiments, systolic blood 

pressure, plasma nitric oxide and estradiol levels, aortic wall thickness, and cholesterol profiles 

were determined after treatment with toremifene. After 4 weeks of treatment, a marked 

improvement in the cardiovascular status of menopause-induced rats was observed as evidenced 

by decreased blood pressure, restoration of smooth muscle function and structure in vascular 

walls, and modified serum lipid profiles. This study provides evidence that toremifene may be 

beneficial to the cardiovascular system following menopause in this animal model. 

Jorge Gonzalez-Perez and Maria Crespo. Chronic Effects of toremifene on the vasculature of 

menopause-induced rats. Vascular Pharmacology. 40:261-268 (2004). 

Insulin, physical activity, and caloric intake in postmenopausal women: breast cancer 

implications

Increased physical activity and programs to reduce body mass index (BMI) with both increased 

physical activity and decreased caloric intake have been proposed to reduce insulin as a potential 

mediator of breast cancer and other chronic diseases. Researchers at the Los Angeles

Biomedical Research Institute at Harbor-UCLA, selected an ethnically diverse subsample of

2,996 mostly healthy postmenopausal women with no prior cancer history from the participants 

in the Women’s Health Initiative clinical trials and observational study. Information was 

collected on diet, recreational physical activity, and BMI. Using a cross-sectional design, insulin 

levels were compared across quintiles of caloric intake and physical activity. Lower BMI, lower 

caloric intake, and higher levels of physical activity were all independently associated with lower 

mean fasting insulin levels. These findings suggest that reduction in BMI achieved through 

184 
 

increasing physical activity, reducing caloric intake, or both, should lower insulin levels, 

providing support for clinical trials evaluating insulin level change and breast cancer risk.

R.T. Chlebowski, M. Pettinger, M.L. Stefanick, B.V. Howard, Y. Mossavar-Rahmani, and A. 

McTiernan. Journal of Clinical Oncology. 22(22):4507-4513 (2004). 

Mechanism of increased bone loss after menopause 

Loss of bone density after menopause is a well-known risk factor for fractures. The mechanisms

are known to involve reduced levels of estrogen in the blood that allow increased bone 

breakdown. The cells that make and break down bone are controlled by several locally-acting 

hormones called paracrine mediators, of which RANKL is the final common pathway. 

Researchers at the Mayo Clinic, with support from the NCRR, isolated cells from the bone 

marrow of premenopausal and postmenopausal women who were, or were not, taking an 

estrogen replacement. The marrow cells were tested for RANKL on their surfaces. The surface 

concentration of RANKL per cell was highest in the untreated compared with the estrogentreated postmenopausal women and the premenopausal women. These data are consistent with 

the view that an increase in RANKL expression on bone marrow cellsis an important 

determinant of increased bone breakdown induced by estrogen deficiency. This information on 

the cell and molecular biology underlying changes in bone density may lead to future treatments 

to reduce the risk of bone fractures in postmenopausal women. 

Guitty Eghbali-Fatourechi, Sundeep Khosla, Arunik Sanyal, William J. Boyle, David L. Lacey 

and B. Lawrence Riggs. Role of RANK ligand in mediating increased bone resorption in early 

 postmenopausal women J. Clin. Invest. 111:1221-1230 (2003). 

Walking to control weight among overweight and obese post menopausal women

Obesity is increasingly common and is accompanied by increases in the prevalence of diabetes, 

hypertension and cardiac disease. Exercise is known to contribute to weight loss, but the duration 

and kind of exercise have not been defined. Researchers at the University of Washington Clinical 

Research Center, with funding from the NCRR, participated in a study that sought to determine 

whether the equivalent of three hours of brisk walking per week would affect weight and intraabdominal body fat. The study took the form of a randomized controlled trial (conducted from

1997 to 2001) of 173 sedentary, overweight postmenopausal women aged 50 to 75 years who 

were living in the Seattle area. One group of 87 women participated in moderate-intensity sports 

and recreational activity for a mean of 3.5 days/wk for 176 min/wk. Walking was the most 

frequently reported activity. After 12 months, the exercisers were an average of 1.4 kg lighter 

than the 86 women who performed only stretching exercises. The exercise group also lost about 

1.0% of their total body fat. Greater body fat loss was observed with increasing duration of 

exercise. The researchers concluded that regular exercise such as brisk walking resultsin reduced 

body weight and body fat among overweight and obese postmenopausal women.

Melinda L. Irwin, PhD, MPH; Yutaka Yasui, PhD; Cornelia M. Ulrich, PhD; Deborah Bowen, 

PhD; Rebecca E. Rudolph, MD, MPH; Robert S. Schwartz, MD; Michi Yukawa, MD; Erin 

Aiello, MPH; John D. Potter, MD, PhD; Anne McTiernan, MD, PhD. Effect of Exercise on Total 

and Intra-abdominal Body Fat in Postmenopausal Women. A Randomized Controlled Trial 

JAMA. 289:323-330 (2003). 

Hormone Replacement Therapy and Metabolic Cardiovascular Risk 

185 
 

186 

After menopause, women gain body fat particularly in the intra-abdominal cavity and 

become less sensitive to insulin, increasing their risk of developing diabetes mellitus 

and cardiovascular disease. Investigators at the University of Vermont have sought to 

determine whether hormone replacement therapy reduces intra-abdominal and 

subcutaneous abdominal fat and improved insulin sensitivity in postmenopausal 

women. In the 2-year randomized, double-blind placebo-controlled trial 76 women 

received conjugated estrogens (0.625 mg) plus progesterone at baseline, 6 months, 1 

year, and 2 year time points. DEXA scan was used to determine body composition, and 

a euglycemic hyperinsulinemic clamp was used to measure insulin sensitivity. The 

investigators found that HRT did not have an effect on intra- abdominal fat, 

subcutaneous abdominal fat, total fat, percent fat, lean body mass, or weight. However, 

insulin sensitivity decreased significantly in the HRT group compared to the placebo 

group (p=0.02). The study conclusions suggest that estrogen plus progestin 

replacement therapy reduces insulin sensitivity without affecting body composition or 

body fat distribution. 

C.K. Sites, M.J. Toth, M. Cushman, G.D. L'Hommedieu, A. Tchernof, R.P. 

Tracy, E.T. Poehlman. Menopause-related differences in inflammation 

markers and their relationship to body fat distribution and insulin-stimulated 

glucose disposal. Fertil Steril. 77:128-135 (2002). 

Effects of estrogen replacement therapy on bone turnover in ovariectomized cynomolgus 

monkeys. 

Over the past 9 years, the investigators have developed and analyzed a monkey model of 

menopause, particularly as is relates to conditions affecting the skeletal system. Ovariectomized 

cynomologus monkeys develop osteoporosis and osteoarthritis, similar to post-menopausal 

women. Most recently, the investigators have examined the effects of estrogen replacement 

therapy on subchondral bone of the proximal tibia in these animals. The subchondral bone 

directly underlies the articular cartilage and previous studies suggest that changes in this area of 

bone affects the health of the overlying cartilage, and thus the potential severity of osteoarthritis. 

The current studies show that bone turnover is decreased by estrogen replacement therapy and 

also that soy phytoestrogens help preserve bone volume in the absence of estrogen. The monkey 

model can thus be used to examine many aspects of the physiological effects of estrogen 

replacement therapy on the skeletal system during menopause. 

K.D. Ham and C.S. Carlson, “Effects of estrogen replacement therapy on bone turnover in 

subchondral bone and epiphyseal metaphyseal cancellous bone of ovariectomized cynomolgus 

monkeys. J. of Bone and Mineral Research.19: 823-829 (2004). 

NCRR MENOPAUSE RESEARCH RELATED GRANTS – FY 2002-2004 

GRANT 

NUMBER TITLE PI INSTITUTION 

G12 

RR003051 

ACT 5 III: WOMEN HEALTH: MENOPAUSE & 

HEALTH IN HISPANIC WOMEN IN PUERTO RICO 

ROMAGUERA, 

JOSEFINA 

UNIVERSITY OF 

PUERTO RICO 

MED SCIENCES 

G12 

RR013646 

P2: ESTROGEN REPLACEMENT THERAPY & 

NEURON STRUCTURE: ALZHEIMERS 

CLAIBORNE, 

BRENDA J 

UNIVERSITY OF 

TEXAS SAN 
 ANTONIO 

K01 

RR000170 

NON HUMAN PRIMATE MODEL OF NATURAL 

MENOPAUSE CARDIOVASCULAR DIS 

OSTEOPOROSIS 

HONORE, ERIKA K 

SOUTHWEST

FOUNDATION FOR 

BIOMEDICAL RES 

K23 

RR016067 

WOMEN AT HIGH RISK FOR CAD AFTER 

MENOPAUSE: BENEFITS OF ERT CARR, MOLLY C UNIVERSITY OF

WASHINGTON 

K23 

RR016321 

POSTMENOPAUSAL HORMONAL REPLACEMENT

THERAPY SYMPATHIC NERVE & HYPERTESION 

VONGPATANASIN, 

WANPEN 

UNIVERSITY OF

TEXAS SW MED 

CTR/DALLAS 

K23 

RR017043 

NEUROBIOLOGICAL EFFECT OF LONG-TERM

ESTROGEN REPLACEMENT 

SMITH, YOLANDA

R 

UNIVERSITY OF

MICHIGAN AT 

ANN ARBOR 

M01 

RR000030 

HEART DISEASE IN WOMEN: ESTROGEN 

EFFECTS ON HEMODYNAMICS 

SHERWOOD, 

ANDREW 

UNIVERSITY OF

PENNSYLVANIA 

UNIVERSITY OF

MICHIGAN AT 

ANN ARBOR 

DUKE 

UNIVERSITY 

M01 

RR000032 POST MENOPAUSAL HORMONE THERAPY GOWER, BARBARA 

UNIVERSITY OF

ALABAMA AT

BIRMINGHAM 

M01 

RR000034 

IMPACT OF ENZYME-INDUCING ANTIEPILEPTIC 

DRUGS ON HORMONE REPLACEMENT THERAPY

MCAULEY, JAMES 

W 

OHIO STATE

UNIVERSITY 

M01 

RR000037 FOLLICLE DEVELOPMENT STUDY KLEIN, NANCY UNIVERSITY OF

WASHINGTON 

M01 

RR000037 

ESTROGENS, BODY FAT AND DYSLIPIDEMIA AT

MENOPAUSE CARR, MOLLY UNIVERSITY OF

WASHINGTON 

M01 

RR000037 

SLEEP IN OLDER WOMEN: EFFECTS OF 

ESTROGEN MOE, KAREN UNIVERSITY OF

WASHINGTON 

M01 

RR000037 

EXERCISE EFFECTS ON HORMONES IN POSTMENOPAUSAL WOMEN MCTIERNAN, ANNE UNIVERSITY OF

WASHINGTON 

M01 

RR000040 

THE EFFECTS OF ESTROGEN AND DHEA 

SUPPLEMENTATION ON SERUM LIPIDS, & 

MUSCLE MASS 

BARNHART, KURT

M01 

RR000040 

NMR IMAGING AND STEROLOGIC ANALYSIS OF

TRABECULAR BONE WEHRLI, FELIX UNIVERSITY OF

PENNSYLVANIA 

M01 

RR000042 

ROLE OF GLUCOSE IN MENOPAUSAL HOT 

FLASHES 

DORMIRE, SHARON

L 

UNIVERSITY OF

MICHIGAN AT 

ANN ARBOR 

M01 

RR000042 

SAFETY OF ESTROGENS IN LUPUS 

ERYTHEMATOSUS NATIONAL ASSESSMENT 

(SELENA) 

MCCUNE, WILLIAM

J 

UNIVERSITY OF

MICHIGAN AT 

ANN ARBOR 

M01 

RR000042 

EFFECT OF TRANSDERMAL ESTROGEN & ORAL 

ISOFLAVONE ON SEX HORMONE-BINDING

GLOBULIN 

LEE, CATHY C 

187 
 

M01 

RR000042 

THE ROLE OF HYPOTHALAMIC AGING IN

MENOPAUSE REAME, NANCY E 

UNIVERSITY OF

MICHIGAN AT 

ANN ARBOR 

M01 

RR000042 

AGE AND MENOPAUSE EFFECTS ON

INDICATORS OF BONE HEALTH LUKACS, JANE L 

UNIVERSITY OF

MICHIGAN AT 

ANN ARBOR 

M01 

RR000046 WOMEN'S HEALTH INITIATIVE HEISS, GERARDO 

UNIVERSITY OF

NORTH CAROLINA

CHAPEL HILL

M01 

RR000047 

HORMONE REPLACEMENT THERAPY IN

MENOPAUSAL WOMEN WITH EPILEPSY 

HARDEN, CYNTHIA 

L. 

WEILL MEDICAL 

COLLEGE OF

CORNELL UNIV 

M01 

RR000048 

EPIDEMIOLOGY OF OSTEOPOROSIS IN WOMEN

WITH LUPUS - MAMDC PROJECT 

RAMSEYGOLDMAN, 

ROSALIND 

NORTHWESTERN 

UNIVERSITY 

M01 

RR000051 

DHEA, SEX STEROIDS AND COGNITION IN POSTMENOPAUSAL WOMEN HIRSHMAN, ELLIOT COLOR

UNIVERSITY OF

ADO HLTH 

SCIENCES CTR 

UNIVERSITY OF

COLORADO HLTH 

SCIENCES CTR 

UNIVERSITY OF

COLORADO HLTH 

SCIENCES CTR 

OHNS HOPKINS 

IVERSITY 

UNIVERSITY OF

PITTSBURGH AT 

PITTSBURGH 

M01 

RR000051 

INFLUENCE OF HORMONE REPLACEMENT 

THERAPY ON ARTERIAL

FUNCTION/STRUCTURE 

MOREAU, KERRIE 

UNIVERSITY OF

COLORADO HLTH 

SCIENCES CTR 

M01 

RR000051 

MODULATION OF WHOLE BODY AND 

REGIONAL ADIPOSE TISSUE LIPOLYSIS AFTER 

MENOPAUSE 

KOHRT, WENDY 

UNIVERSITY OF

COLORADO HLTH 

SCIENCES CTR 

M01 

RR000051 

MECHANISMS OF VISCERAL FAT 

ACCUMULATION IN OLDER WOMEN 

GOZANSKY,

WENDEE 

M01 

RR000051 

MODULATION OF VISCERAL FAT BY 

ESTROGENS AFTER MENOPAUSE KOHRT, WENDY 

M01 

RR000052 

EFFECT OF HORMONE REPLACEMENT ON THE 

PROGRESSION OF ATHEROSCLEROSIS... OUYANG, PAMELA 

J

UN

M01 

RR000054 

SELECTIVE ESTROGEN RECEPTOR

MODULATION: EFFECTS IN POST-MENOPAUSAL

WOMEN 

UDELSON, JAMES 

NEW ENGLAND 

MEDICAL CENTER 

HOSPITALS 

M01 

RR000056 

THE EFFECT OF PHYTOESTROGEN 

SUPPLEMENTATION ON POST-MENOPAUSAL 

ENDOMETRIUM 

BALK, JUDY 

M01 

RR000056 

CIRCULATING ANDROGENS LEVELS IN

POSTMENOPAUSAL WOMEN W/POLYCYSTIC 

OVARY SYNDROME 

KORYTKOWSKI, 

MARY 

UNIVERSITY OF

PITTSBURGH AT 

PITTSBURGH 

M01 

RR000056 WOMEN'S HEALTH INITIATIVE KULLER, LEWIS 

UNIVERSITY OF

PITTSBURGH AT 

PITTSBURGH 

188 
 

M01 

RR000056 

RANDOMIZED DBL-BLIND...HORMONE

REPLACEMENT IN POSTMENOPAUSAL WOMEN

W/SLE 

MANZI, SUSAN

UNIVERSITY OF

PITTSBURGH AT 

PITTSBURGH 

VIRGINIA

COMMONWEALTH 

UNIVERSITY 

VIRGINIA

COMMONWEALTH 

UNIVERSITY 

UNIVERSITY OF

TEXAS MEDICAL 

BR GALVESTON 

CASE WESTERN 

UNIVERSITY

VANDERBILT 

UNIVERSITY 

M01 

RR000056 HORMONE METABOLISM AND BREAST MASSES MODUGNO,

FRANCESMARY 

UNIVERSITY OF

PITTSBURGH AT 

PITTSBURGH 

M01 

RR000056 

A FUNCTIONALLY BASED APPROACH TO THE

TREATMENT OF INCONTINENCE 

BORELLO-FRANCE,

DIANE 

UNIVERSITY OF

PITTSBURGH AT 

PITTSBURGH 

M01 

RR000058 

CLINICAL TRIAL AND OBSERVATIONAL STUDY 

OF THE WOMEN'S HEALTH INITIATIVE KOTCHEN, JANE

MEDICAL 

COLLEGE OF

WISCONSIN 

M01 

RR000059 THE WOMEN'S HEALTH INITIATIVE WALLACE, ROBERT 

B. 

UNIVERSITY OF

IOWA 

M01 

RR000065 

PERIPHERAL VASCULAR ENDOTHELIAL 

FUNCTION AFTER MENOPAUSE 

ARROWOOD, 

JAMES 

M01 

RR000065 

INSULIN RESISTANCE & CARDIOVASCULAR 

RISK IN POSTMENOPAUSAL WOMEN WITH PCOSNESTLER, JOHN E 

VIRGINIA

COMMONWEALTH 

UNIVERSITY 

M01 

RR000065 

PROGESTERONE ADMINISTRATION ON

ENDOTHELIAL FUNCTION IN 

POSTMENOPAUSAL WOMEN 

ARROWOOD, 

JAMES 

M01 

RR000073 

OVARIAN STEROIDS IN MENOPAUSAL WOMEN

WITH ENDOMETRIAL CANCER 

NAGAMANI,

MANUBAI 

M01 

RR000073 

EFFECT OF RALOXIFENE ON INSULIN 

SENSITIVITY IN NORMAL POSTMENOPAUSAL

WOMEN 

NAGAMANI,

MANUBAI 

UNIVERSITY OF

TEXAS MEDICAL 

BR GALVESTON 

M01 

RR000080 

SOY PHYTOESTROGEN AND CALCIUM

SUPPLEMENTATION ON BONE

RESORPTION/FORMATION 

HARKNESS, LAURA RESERVE 

M01 

RR000095 

THE EFFECTS OF 3 DIFFERENT DOSES OF

ENTERIC COATED BAYER ASPIRIN ON LEVELS

OF 

KERINS, DAVID 

M01 

RR000109 

ESTROGEN MODULATION EFFECTS ON 

CHOLINERGIC FUNCTION IN POSTMENOPAUSAL WOMEN 

NEWHOUSE, PAUL 

A 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

M01 

RR000109 

EFFECT OF HRT ON CARDIOVASCULAR

HEMODYNAMICS IN MENOPAUSAL WOMEN SITES, CYNTHIA K 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

M01 

RR000109 

MECHANISM OF MUSCLE PROTEIN LOSS IN 

MENOPAUSE 

MATTHEWS, 

DWIGHT E 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

189 
 

M01 

RR000109 

ESTROGEN AND MOOD AND COGNITION

FOLLOWING MONOAMINERGIC DEPLETION 

NEWHOUSE, PAUL 

A 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

M01 

RR000109 

ESTROGEN AND CHOLINERGIC FUNCTION IN

NORMAL POST-MENOPAUSAL WOMEN 

NEWHOUSE, PAUL 

A 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

BAYLOR 

COLLEGE OF

MEDICINE 

OREGON HEALTH

UNIVERSITY 

HARBOR-UCLA 

RESEARCH & 

EDUC INST 

RR000585 

MAYO CLINIC 

ROCHESTER 

RR000585 

RIGGS, B 

LAWRENCE 

MAYO CLINIC 

ROCHESTER 

M01 

M01 

RR000109 

HORMONE REPLACEMENT THERAPY AND 

METABOLIC CARDIOVASCULAR RISK SITES, CYNTHIA K 

UNIVERSITY OF

VERMONT & ST 

AGRIC COLLEGE 

M01 

RR000109 

ENERGY METABOLISM DURING THE 

MENOPAUSE TRANSITION 

MATTHEWS, 

DWIGHT E 

M01 

RR000109 

HRT TO AUGMENT LOSS OF VISCERAL FAT AND 

IMPROVE INSULIN SENSITIVITY 

MATTHEWS, 

DWIGHT E 

M01 

RR000125 

PERIMENOPAUSAL SYMPTOMS MANAGEMENT

WITH ACUPUNCTURE 

COHEN, SUSAN

DSN 

YALE 

UNIVERSITY 

M01 

RR000188 

EFFECTS OF SOY ISOFLAVONES ON NITRIC

OXIDE PRODUCTION IN POSTMENOPAUSAL 

WOMEN 

WONG, WILLIAM

M01 

RR000334 

STUDY OF TAMOXIFEN AND RALOXIFENE

(STAR) FOR BREAST CANCER PREVENTION NICHOLS, CRAIG 

OREGON HEALTH

& SCIENCE

UNIVERSITY 

M01 

RR000334 

BREAST CANCER SURVIVORS: EXERCISE AND 

RALOXIFENE SCHWARTZ, ANNA & SCIENCE

M01 

RR000400 

SOY, PROBIOTICS, AND BREAST CANCER 

PREVENTION KURZER, MINDY 

UNIVERSITY OF

MINNESOTA TWIN

CITIES 

M01 

RR000425 

CLINICAL TRIAL&OBSERVATIONAL STUDY OF 

WOMEN'S HEALTH INITIATIVE-WEST 

CHLEBOWSKI, 

ROWAN T 

M01 

RR000585 SEROLOGIC SERBB1 IN HEALTHY WOMEN BARON, ANDRE T MAYO CLINIC 

ROCHESTER 

M01 BONE DENSITY AMONG HISPANIC OLMSTED

COUNTY RESIDENTS: A CROSS-SECTIONAL AND 

LON 

RIGGS, B 

LAWRENCE 

M01 MECHANISM OF INCREASED 

OSTEOCLASTOGENESIS DURING ESTROGEN 

DEFICIENCY 

EGHBALI, GUITI Z MAYO CLINIC 

ROCHESTER 

M01 

RR000585 

THE ROLE OF PARATHYROID HORMONE (PTH) 

IN AGE-RELATED CHANGES IN BONE 

TURNOVER 

SIMVASTIN/HRT IN POSTMENOPAUSAL WOMEN GARG, UNIVERSITY OF

190 
 

191 

RR000633 

RALOXIFENE IN PRIMARY 

HYPERPARATHYROIDISM 

RR000645 

THE CHOICE PROJECT: COMPARING HEALTHY 

OPTIONS IN COOKING AND EATING BILEZIKIAN, JOHN 

COLUMBIA 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR000645 

THE EFFECTS OF HORMONE REPLACEMENT 

THERAPY IN DIABETIC WOMEN 

UNIVERSITY OF 

CALIFORNIA SAN 

DIEGO 

KRITZ-SILVERSTE, 

DONNA 

WITH NIDDM ABHIMANYU TEXAS SW MED 

CTR/DALLAS 

M01 

RR000645 

THE FIBRINOLYTIC POTENTIAL OF ESTROGEN 

IN WOMEN 

GIARDINA, ELSAGRACE V 

COLUMBIA 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR000645 

SILVERBERG, 

SHONNI J 

COLUMBIA 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR000645 BLACK COHOSH AND HOT FLASHES KRONENBERG, 

FREDI 

COLUMBIA 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

TUCK, CATHERINE 

COLUMBIA 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR000645 

ALZHEIMER’S DISEASE PREVENTION TRIAL 

WITH ESTROGEN SANO, MARY 

COLUMBIA 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR000827 

GENDER DIFFERENCES IN SUSCEPTIBILITY TO 

FATTY ACID INDUCED INSULIN RESISTANCE 

KRUSZYNSKA, 

YOLANTA 

UNIVERSITY OF 

CALIFORNIA SAN 

DIEGO 

M01 

RR000827 

HEALTH EFFECTS OF POSTMENOPAUSAL 

PHYTOESTROGEN USE 

KRITZ-SILVERSTE, 

DONNA 

M01 

RR000827 

SOY AND POSTMENOPAUSAL HEALTH IN 

AGING (SOPHIA) 

UNIVERSITY OF 

CALIFORNIA SAN 

DIEGO 

M01 

RR000827 

HORMONE REPLACEMENT THERAPY AND 

ADRENERGIC PHYSIOLOGY MILLS, PAUL J 

UNIVERSITY OF 

CALIFORNIA SAN 

DIEGO 

M01 

RR000833 

MELATONIN TREATMENT FOR SLEEP 

DISTURBANCES DURING MENOPAUSE DARKO, DENIS F 

SCRIPPS 

RESEARCH 

INSTITUTE 

M01 

RR000847 

SEX-STEROID CONTROL OF GH FEEDBACK ON 

EXERCISE 

VELDHUIS, 

JOHANNES D 

UNIVERSITY OF 

VIRGINIA 

CHARLOTTESVILL

E 

M01 EFFECTS OF AGE ON HYPOTHALAMICPITUITARY-OVARIAN ACTIVITY IN NORMAL EVANS, WILLIAM S UNIVERSITY OF 

VIRGINIA 
 

192 

RR000865 

PILOT PROJECT TO STUDY HRT, HPA AXIS 

REACTIVITY AND MEMORY FUNCTION 

HORMONE REPLACEMENT IN MENOPAUSAL 

WOMEN WITH EPILEPSY 

L, JANET E 

M01 A GNRH ANTAGONIST (NAL-GLU GNRH 

ANTAGONIST) IN PMW 

RR002558 

SAFETY OF ESTROGENS IN LUPUS 

ERYTHEMATOSUS - NATIONAL ASSESSMENT 

FRIEDMAN, ALAN 

W 

M01 

MAKI, PAULINE 

M01 

RR000847 WOMEN CHARLOTTESVILL

E 

M01 SEEMAN, TERESA 

UNIVERSITY OF 

CALIFORNIA LOS 

ANGELES 

M01 

RR001032 

THE ROLE OF ESTROGEN ON VASCULAR 

FUNCTION IN INSULIN RESISTANT WOMEN 

GOLDFINE, 

ALLISON B 

BETH ISRAEL 

DEACONESS 

MEDICAL CENTER 

M01 

RR001032 

HERZOG, ANDREW 

G 

BETH ISRAEL 

DEACONESS 

MEDICAL CENTER 

M01 

RR001066 

RALOXIFENE ON BNE MASS & SERUM 

PROLACTIN LVLS/MENOPAUSAL WM 

W/HYPERPROLACTINEMIA 

KLIBANSKI, ANNE 

MASSACHUSETTS 

GENERAL 

HOSPITAL 

M01 

RR001066 

PITUITARY CONTRIBUTION TO THE DECLINE IN 

GONADOTROPIN SECRETION WITH AGE HAL

MASSACHUSETTS 

GENERAL 

HOSPITAL 

RR001066 HALL, JANET E 

MASSACHUSETTS 

GENERAL 

HOSPITAL 

M01 

RR001346 

EFFECT OF JUMPING EXERCISE INTERVENTION 

BONE MINERAL DENSITY IN POST MENOP WMN NEWSTEAD, ANN 

UNIVERSITY OF 

TEXAS HLTH SCI 

CTR SAN ANT 

M01 

RR002558 BUCCAL ESTROGEN IN TOOTHPASTE STUDY ALI, VASEEM 

UNIVERSITY OF 

TEXAS HLTH SCI 

CTR HOUSTON 

M01 UNIVERSITY OF 

TEXAS HLTH SCI 

CTR HOUSTON 

RR002602 

EFFECT OF PROGESTOGENS ON BONE AND 

COGNITION MUSE, KEN UNIVERSITY OF 

KENTUCKY 

M01 

RR002635 

ADDITION OF TESTOSTERONE TO HRT 

ENHANCES QOL AND LIBIDO IN 

POSTMENOPAUSAL WOMEN 

GINSBURG, 

ELIZABETH S 

BRIGHAM AND 

WOMEN'S 

HOSPITAL 

M01 

RR002719 

EFFECTS OF SEX HORMONE REPLACEMENT 

THERAPY ON COGNITION & MOOD IN OLDER 

ADULTS 

MAKI, PAULINE JOHNS HOPKINS 

UNIVERSITY 

M01 

RR002719 

HORMONE REPLACEMENT THERAPY AFTER 

CORONARY ARTERY BYPASS SURGERY OUYANG, PAMELA JOHNS HOPKINS 

UNIVERSITY 

M01 

RR002719 

ESTROGEN/SERMS EFFECTS ON COGNITION 

AND BRAIN FUNCTION 

JOHNS HOPKINS 

UNIVERSITY 

RR002719 

WOMEN'S ANGIOGRAPHIC VITAMINS AND 

ESTROGEN (WAVE) TRIAL OUYANG, PAMELA JOHNS HOPKINS 

UNIVERSITY 

M01 BLSA: PERIMENOPAUSAL INITIATIVE BELLANTONI, JOHNS HOPKINS 
 

193 

M01 

RAISZ, LAWRENCE 

G 

KI-67 LEVELS IN BREAST CORE BIOPSY 

SPECIMENS FROM POSTMENOPAUSAL WOMEN 

M01 

RR002719 MICHELE F UNIVERSITY 

M01 

RR003186 

WOMEN'S HEALTH INITIATIVE -- UNIVERSITY 

OF WISCONSIN-MADISON CLINICAL CENTER 

ALLEN, 

CATHERINE I 

UNIVERSITY OF 

WISCONSIN 

MADISON 

RR005096 

EFFECTS OF ESTROGEN REPLACEMENT IN TYPE 

2 DIABETES FRIDAY, KAREN E. 

TULANE 

UNIVERSITY OF 

LOUISIANA 

M01 

RR006192 

EFFECT OF HORMONE REPLACEMENT THERAPY

ON BONE IN OLDER WOMEN 

PRESTWOOD, 

KAREN 

UNIVERSITY OF 

CONNECTICUT 

SCH OF MED/DNT 

M01 

RR006192 

TRANSDERMAL PROGESTERONE ON BONE 

TURNOVER 

UNIVERSITY OF 

CONNECTICUT 

SCH OF MED/DNT 

M01 

RR007122 VITOLINS, MARA Z 

WAKE FOREST 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR007122 

WOMEN'S HEALTH INITIATIVE MEMORY STUDY 

(WHIMS) VITOLINS, MARA Z 

WAKE FOREST 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR007122 

POSTMENOPAUSAL HORMONE REPLACEMENT 

THERAPY AFTER CORONARY BYPASS SURGERY

(EAGER) 

HERRINGTON, 

DAVID M 

WAKE FOREST 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR007122 

VASOMOTOR EFFECT OF HORMONAL 

REPLACEMENT REGIMENS 

HUNDLEY, W 

GREGORY 

WAKE FOREST 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR007122 

WOMEN'S HEALTH INITIATIVE (WHI) 

VANGUARD CLINICAL CENTER TRIAL 

BURKE, GREGORY 

L 

WAKE FOREST 

UNIVERSITY 

HEALTH 

SCIENCES 

M01 

RR010284 ALZHEIMER—ESTROGEN OBISESAN, 

THOMAS O 

HOWARD 

UNIVERSITY 

M01 

RR010732 

EFFECTS OF THE GLYCEMIC INDEX OF FOODS 

ON CVD RISK IN POST MENOPAUSAL WOMEN 

PELKMAN, 

CHRISTINE L 

PENNSYLVANIA 

STATE UNIV 

HERSHEY MED 

CTR 

RR010732 

NUTRITIONAL STUDY IN POST MENOPAUSAL 

WOMEN 

KRIS-ETHERTON, 

PENNY M 

PENNSYLVANIA 

STATE UNIV 

HERSHEY MED 

CTR 

M01 

RR010732 

EFFECTS OF THE GLYCEMIC INDEX OF FOODS 

ON CVD RISK IN POST-MENOPAUSAL WOMEN 

PELKMAN, 

CHRISTINE L 

PENNSYLVANIA 

STATE UNIV 

HERSHEY MED 
 CTR 

M01 

RR013987 

A PHASE I STUDY OF BLACK COHOSH AND RED 

CLOVER IN HEALTHY MENOPAUSAL WOMEN 

SHULMAN, LEE 

PHILLIP 

UNIVERSITY OF

ILLINOIS AT 

CHICAGO 

N02 

RR001132 CLINICAL RESEARCH LRP GOZANSKY,

WENDOLYN S 

UNIVERSITY OF

COLORADO 

HEALTH SCI CTR 

P20 

RR015592 

KY COBRE: ACTIONS OF ESTRADIOL & SERMS

ON COGNITION, MOOD & EFFECT KELLY, THOMAS UNIVERSITY OF

KENTUCKY 

P41 

RR000862 

AMYLOIDOSIS IN RESPONSE TO OVARIECTOMY

IN TRANSGENIC MODEL OF ALZHEIMERS

DISEASE 

DUFF, KAREN ROCKEFELLER 

UNIVERSITY 

P41 

RR000954 

WEIGHT LOSS & RESISTANCE TRAINING ON

INSULIN ACTION IN POSTMENOPAUSAL 

WOMEN 

JOSEPH, LYNDON 

JO 

WASHINGTON

UNIVERSITY 

P41 

RR000954 

BONE DENSITY RESPONSE TO ESTROGEN

REPLACEMENT IN ELDERLY WOMEN 

VILLAREAL,

DENNIS T 

WASHINGTON

UNIVERSITY 

P41 

RR001192 

BREAST CANCER DETECTION USING 

FREQUENCY DOMAIN PHOTON MIGRATION BUTLER, JOHN A 

UNIVERSITY OF

CALIFORNIA 

IRVINE 

P41 

RR011623 

MECHANISMS OF RADIATION INDUCED

OOCYTE LOSS 

TILLY, JONATHAN 

Z 

COLUMBIA 

UNIVERSITY

HEALTH

SCIENCES 

P51 

RR000163 

OVARIAN STEROID REGULATION OF 

SEROTONIN NEURAL FUNCTION

BETHEA, CYNTHIA 

L 

OREGON HEALTH

& SCIENCE

UNIVERSITY 

P51 

RR000163 

COGNITION AND ESTROGEN IN MIDDLE-AGED

FEMALE MONKEYS VOYTKO, MARY 

OREGON HEALTH

& SCIENCE

UNIVERSITY 

EFFECTS OF ESTROGENS ON COGNITION IN

YOUNG FEMALE RHESUS 

P51 

P51 

RR000165 

EFFECTS OF ESTROGENS AND RALOXIFENE ON

COGNITION IN AGED FEMALE RHESUS

MONKEYS 

LACREUSE, AGNES EMORY 

UNIVERSITY 

P51 

RR000165 LACREUSE, AGNES EMORY 

UNIVERSITY 

P51 

RR000169 COGNITIVE FUNCTION IN THE AGED MONKEY RAPP, PETER R 

UNIVERSITY OF

CALIFORNIA 

DAVIS 

RR000169 

TREATMENT OF OVARIECTOMIZED-INDUCED 

BONE LOSS IN CYNOMOLGUS MONKEYS 

HENDRICKX,

ANDREW G 

UNIVERSITY OF

CALIFORNIA 

DAVIS 

P51 

RR000169 ESTROGEN & AGING BRAIN MORRISON, JOHN 

UNIVERSITY OF

CALIFORNIA 

DAVIS 

194 
 

P51 

RR013986 

ESTABLISHMENT OF AN OSTEOPENIC COLONY 

OF FEMALE BABOONS CAREY, K DEE 

R01 

SOUTHWEST

FOUNDATION FOR 

BIOMEDICAL RES 

P51 

RR013986 

A PILOT STUDY OF THE PHYSIOLOGY OF THE 

PERIMENOPAUSE IN BABOONS HONORE, ERIKA K 

SOUTHWEST

FOUNDATION FOR 

BIOMEDICAL RES 

P51 

RR013986 

A NONHUMAN PRIMATE MODEL OF NATURAL 

MENOPAUSE HONORE, ERIKA K 

SOUTHWEST

FOUNDATION FOR 

BIOMEDICAL RES 

RR014099 

NEW TECHNIQUES IN DIAGNOSING

OSTEOARTHRITIS: MENOPAUSE 

CARLSON, CATHY 

SUE 

UNIVERSITY OF

MINNESOTA TWIN

CITIES 

R24 

RR016535 

THE YUCATAN MICROPIG CARDIOVASCULAR

MODEL OF MENOPAUSE: SOY DIET 

GOODRICH, JAMES 

A 

MEDICAL 

UNIVERSITY OF

SOUTH CAROLINA

195 
GRANT NUMBER

G12RR003051 

TITLE PRI

ACT 5 III: WOMEN HEALTH: MENOPAUSE & HEALTH IN HISPANIC WOMEN IN PUERTO RICO ROM

G12RR013646 

M01RR000030M01RR000034

M01RR000036

M01RR000040

GLOBULIN

NE HEALTH LUK

ERAPY IN MENOPAUSAL WOMEN WITH EPILEPSY 

RAM

TION/STRUCTURE 

MODULATION OF WHOLE BODY AND REGIONAL ADIPOSE TISSUE LIPOLYSIS AFTER MENOPAUSE

MECHANISMS OF VISCERAL FAT ACCUMULATION IN OLDER WOMEN 

P2: ESTROGEN REPLACEMENT THERAPY & NEURON STRUCTURE: ALZHEIMERS CLA

K01RR000170 

K23RR016067 

NON HUMAN PRIMATE MODEL OF NATURAL MENOPAUSE CARDIOVASCULAR DIS OSTEOPOROSIS HON

WOMEN AT HIGH RISK FOR CAD AFTER MENOPAUSE: BENEFITS OF ERT CAR

K23RR016321 

K23RR017043 

POSTMENOPAUSAL HORMONAL REPLACEMENT THERAPY SYMPATHIC NERVE &HYPERTESION VON

NEUROBIOLOGICAL EFFECT OF LONG-TERM ESTROGEN REPLACEMENT SMI

HEART DISEASE IN WOMEN: ESTROGEN EFFECTS ON HEMODYNAMICS SHE

M01RR000032 POST MENOPAUSAL HORMONE THERAPY GOW

IMPACT OF ENZYME-INDUCING ANTIEPILEPTIC DRUGS ON HORMONE REPLACEMENT THERAPY MCA

WASHINGTON UNIVERSITY CLAUDE D. PEPPER OAIC. HOL

M01RR000037 FOLLICLE DEVELOPMENT STUDY KLEM01RR000037 ESTROGENS, BODY FAT AND DYSLIPIDEMIA AT MENOPAUSE CARM01RR000037 SLEEP IN OLDER WOMEN: EFFECTS OF ESTROGEN MOEM01RR000037 EXERCISE EFFECTS ON HORMONES IN POST-MENOPAUSAL WOMEN MCTM01RR000040 THE EFFECTS OF ESTROGEN AND DHEA SUPPLEMENTATION ON SERUM LIPIDS, & MUSCLE 

MASS BAR

NMR IMAGING AND STEROLOGIC ANALYSIS OF TRABECULAR BONE WEH

M01RR000042 DORM01RR000042 

ROLE OF GLUCOSE IN MENOPAUSAL HOT FLASHES 

SAFETY OF ESTROGENS IN LUPUS ERYTHEMATOSUS NATIONAL ASSESSMENT (SELENA) 

EFFECT OF TRANSDERMAL ESTROGEN & ORAL ISOFLAVONE ON SEX HORMONE-BINDING

MCC

M01RR000042 LEE

M01RR000042 REAM01RR000042

THE ROLE OF HYPOTHALAMIC AGING IN MENOPAUSE 

AGE AND MENOPAUSE EFFECTS ON INDICATORS OF BO

M01RR000046 WOMEN'S HEALTH INITIATIVE

HORMONE REPLACEMENT TH

HEI

M01RR000047 HARM01RR000048 EPIDEMIOLOGY OF OSTEOPOROSIS IN WOMEN WITH LUPUS - MAMDC PROJECT M01RR000051 M01RR000051

DHEA, SEX STEROIDS AND COGNITION IN POST-MENOPAUSAL WOMEN 

INFLUENCE OF HORMONE REPLACEMENT THERAPY ON ARTERIAL FUNC

HIR

MOR

M01RR000051 KOH

M01RR000051M01RR000051

GOZ

MODULATION OF VISCERAL FAT BY ESTROGENS AFTER MENOPAUSE KOH

196 
M01RR000052 EFFECT OF HORMONE REPLACEMENT ON THE PROGRESSION OF ATHEROSCLEROSIS... OUY

M01RR000054 SELECTIVE ESTROGEN RECEPTOR MODULATION: EFFECTS IN POST-MENOPAUSAL WOMEN UDE

THE EFFECT OF PHYTOESTROGEN SUPPLEMENTATION ON POST-MENOPAUSAL 

M01RR000056 ENDOMETRIUM BAL

M01RR000056

ARR

N STEROIDS IN MENOPAUSAL WOMEN WITH ENDOMETRIAL CANCER 

M01RR000073 NAG

CIRCULATING ANDROGENS LEVELS IN POSTMENOPAUSAL WOMEN W/POLYCYSTICOVARY SYNDROME KOR

M01RR000056 WOMEN'S HEALTH INITIATIVE KULM01RR000056

RANDOMIZED DBL-BLIND...HORMONE REPLACEMENT IN POSTMENOPAUSAL WOMEN W/SLE MAN

M01RR000056 HORMONE METABOLISM AND BREAST MASSES MODM01RR000056 A FUNCTIONALLY BASED APPROACH TO THE TREATMENT OF INCONTINENCE BORM01RR000058 CLINICAL TRIAL AND OBSERVATIONAL STUDY OF THE WOMEN'S HEALTH INITIATIVE KOTM01RR000059M01RR000065

THE WOMEN'S HEALTH INITIATIVE WAL

PERIPHERAL VASCULAR ENDOTHELIAL FUNCTION AFTER MENOPAUSE ARR

M01RR000065

M01RR000065

INSULIN RESISTANCE & CARDIOVASCULAR RISK IN POSTMENOPAUSAL WOMEN WITHPCOS NES

PROGESTERONE ADMINISTRATION ON ENDOTHELIAL FUNCTION IN POSTMENOPAUSAL 

WOMEN 

M01RR000073 OVARIA NAG

EFFECT OF RALOXIFENE ON INSULIN SENSITIVITY IN NORMAL POSTMENOPAUSALWOMEN 

M01RR000080

SOY PHYTOESTROGEN AND CALCIUM SUPPLEMENTATION ON BONERESORPTION/FORMATION HAR

M01RR000095 THE EFFECTS OF 3 DIFFERENT DOSES OF ENTERIC COATED BAYER ASPIRIN ON LEVELS OF KERM01RR000109

ESTROGEN MODULATION EFFECTS ON CHOLINERGIC FUNCTION IN POST-MENOPAUSAL WOMEN NEW

M01RR000109 EFFECT OF HRT ON CARDIOVASCULAR HEMODYNAMICS IN MENOPAUSAL WOMEN SITEM01RR000109 MECHANISM OF MUSCLE PROTEIN LOSS IN MENOPAUSE MATM01RR000109 ESTROGEN AND MOOD AND COGNITION FOLLOWING MONOAMINERGIC DEPLETION NEWM01RR000109 ESTROGEN AND CHOLINERGIC FUNCTION IN NORMAL POST-MENOPAUSAL WOMEN NEWM01RR000109M01RR000109 

HORMONE REPLACEMENT THERAPY AND METABOLIC CARDIOVASCULAR RISK SITE

ENERGY METABOLISM DURING THE MENOPAUSE TRANSITION MAT

M01RR000109 HRT TO AUGMENT LOSS OF VISCERAL FAT AND IMPROVE INSULIN SENSITIVITY MATM01RR000125 PERIMENOPAUSAL SYMPTOMS MANAGEMENT WITH ACUPUNCTURE COHM01RR000188

EFFECTS OF SOY ISOFLAVONES ON NITRIC OXIDE PRODUCTION IN POSTMENOPAUSALWOMEN WON

197 
M01RR000334 STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) FOR BREAST CANCER PREVENTION NIC

M01RR000334 BREAST CANCER SURVIVORS: EXERCISE AND RALOXIFENE SCH

RIG

RIG

N/HRT IN POSTMENOPAUSAL WOMEN WITH NIDDM

THE FIBRINOLYTIC POTENTIAL OF ESTROGEN IN WOMEN 

M01RR000400 SOY, PROBIOTICS, AND BREAST CANCER PREVENTION KURM01RR000425 CLINICAL TRIAL&OBSERVATIONAL STUDY OF WOMEN'S HEALTH INITIATIVE-WEST CHLM01RR000585 SEROLOGIC SERBB1 IN HEALTHY WOMEN BARM01RR000585

BONE DENSITY AMONG HISPANIC OLMSTED COUNTY RESIDENTS: A CROSS-SECTIONAL AND LON 

M01RR000585 MECHANISM OF INCREASED OSTEOCLASTOGENESIS DURING ESTROGEN DEFICIENCY EGHM01RR000585

THE ROLE OF PARATHYROID HORMONE (PTH) IN AGE-RELATED CHANGES IN BONE TURNOVER 

M01RR000633 SIMVASTI GARM01RR000645 GIAM01RR000645 RALOXIFENE IN PRIMARY HYPERPARATHYROIDISM SILVM01RR000645 BLACK COHOSH AND HOT FLASHES KROM01RR000645 THE CHOICE PROJECT: COMPARING HEALTHY OPTIONS IN COOKING AND EATING BILEM01RR000645 THE EFFECTS OF HORMONE REPLACEMENT THERAPY IN DIABETIC WOMEN TUCM01RR000645 ALZHEIMER’S DISEASE PREVENTION TRIAL WITH ESTROGEN SANM01RR000827 GENDER DIFFERENCES IN SUSCEPTIBILITY TO FATTY ACID INDUCED INSULIN RESISTANCEKRUM01RR000827 HEALTH EFFECTS OF POSTMENOPAUSAL PHYTOESTROGEN USE KRIM01RR000827 SOY AND POSTMENOPAUSAL HEALTH IN AGING (SOPHIA) KRIM01RR000827 HORMONE REPLACEMENT THERAPY AND ADRENERGIC PHYSIOLOGY MILM01RR000833 MELATONIN TREATMENT FOR SLEEP DISTURBANCES DURING MENOPAUSE DARM01RR000847 SEX-STEROID CONTROL OF GH FEEDBACK ON EXERCISE VELM01RR000847

EFFECTS OF AGE ON HYPOTHALAMIC-PITUITARY-OVARIAN ACTIVITY IN NORMAL WOMEN EVA

M01RR000865 PILOT PROJECT TO STUDY HRT, HPA AXIS REACTIVITY AND MEMORY FUNCTION SEEM01RR001032 THE ROLE OF ESTROGEN ON VASCULAR FUNCTION IN INSULIN RESISTANT WOMEN GOLM01RR001032 HORMONE REPLACEMENT IN MENOPAUSAL WOMEN WITH EPILEPSY HERM01RR001066

RALOXIFENE ON BNE MASS & SERUM PROLACTIN LVLS/MENOPAUSAL WMW/HYPERPROLACTINEMIA KLIB

M01RR001066 PITUITARY CONTRIBUTION TO THE DECLINE IN GONADOTROPIN SECRETION WITH AGE HALM01RR001066 A GNRH ANTAGONIST (NAL-GLU GNRH ANTAGONIST) IN PMW HALM01RR001346

EFFECT OF JUMPING EXERCISE INTERVENTION BONE MINERAL DENSITY IN POST MENOPWMN NEW

M01RR002558 BUCCAL ESTROGEN IN TOOTHPASTE STUDY ALI, 

198 
M01RR002558 SAFETY OF ESTROGENS IN LUPUS ERYTHEMATOSUS - NATIONAL ASSESSMENT FRIE

M01RR002602 EFFECT OF PROGESTOGENS ON BONE AND COGNITION MUSM01RR002635

ADDITION OF TESTOSTERONE TO HRT ENHANCES QOL AND LIBIDO IN POSTMENOPAUSALWOMEN GIN

M01RR002719

EFFECTS OF SEX HORMONE REPLACEMENT THERAPY ON COGNITION & MOOD IN OLDER ADULTS MAK

M01RR002719 HORMONE REPLACEMENT THERAPY AFTER CORONARY ARTERY BYPASS SURGERY OUYM01RR002719 ESTROGEN/SERMS EFFECTS ON COGNITION AND BRAIN FUNCTION MAKM01RR002719 WOMEN'S ANGIOGRAPHIC VITAMINS AND ESTROGEN (WAVE) TRIAL OUYM01RR002719 BLSA: PERIMENOPAUSAL INITIATIVE BELM01RR003186 WOMEN'S HEALTH INITIATIVE -- UNIVERSITY OF WISCONSIN-MADISON CLINICAL CENTER ALLM01RR005096 EFFECTS OF ESTROGEN REPLACEMENT IN TYPE 2 DIABETES FRIDM01RR006192 EFFECT OF HORMONE REPLACEMENT THERAPY ON BONE IN OLDER WOMEN PREM01RR006192 TRANSDERMAL PROGESTERONE ON BONE TURNOVER RAIM01RR007122 KI-67 LEVELS IN BREAST CORE BIOPSY SPECIMENS FROM POSTMENOPAUSAL WOMEN VITOM01RR007122 WOMEN'S HEALTH INITIATIVE MEMORY STUDY (WHIMS) VITOM01RR007122

POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY AFTER CORONARY BYPASS SURGERY (EAGER) HER

M01RR007122M01RR007122

VASOMOTOR EFFECT OF HORMONAL REPLACEMENT REGIMENS HUN

WOMEN'S HEALTH INITIATIVE (WHI) VANGUARD CLINICAL CENTER TRIAL BUR

M01RR010284 ALZHEIMER—ESTROGEN OBIM01RR010732

EFFECTS OF THE GLYCEMIC INDEX OF FOODS ON CVD RISK IN POST MENOPAUSAL WOMEN PEL

M01RR010732 NUTRITIONAL STUDY IN POST MENOPAUSAL WOMEN KRIM01RR010732

EFFECTS OF THE GLYCEMIC INDEX OF FOODS ON CVD RISK IN POST-MENOPAUSAL WOMEN PEL

M01RR013987

A PHASE I STUDY OF BLACK COHOSH AND RED CLOVER IN HEALTHY MENOPAUSALWOMEN SHU

N02RR001132 CLINICAL RESEARCH LRP GOZP20RR015592 KY COBRE: ACTIONS OF ESTRADIOL & SERMS ON COGNITION, MOOD & EFFECT KELP41RR000862 

AMYLOIDOSIS IN RESPONSE TO OVARIECTOMY IN TRANSGENIC MODEL OF ALZHEIMERS DISEASE DUF

P41RR000954 

WEIGHT LOSS & RESISTANCE TRAINING ON INSULIN ACTION IN POSTMENOPAUSALWOMEN JOSE

P41RR000954 BONE DENSITY RESPONSE TO ESTROGEN REPLACEMENT IN ELDERLY WOMEN VILLP41RR001192 BREAST CANCER DETECTION USING FREQUENCY DOMAIN PHOTON MIGRATION BUT

199
P41RR011623 MECHANISMS OF RADIATION INDUCED OOCYTE LOSS TILL

P51RR000163 OVARIAN STEROID REGULATION OF SEROTONIN NEURAL FUNCTION BETP51RR000163 COGNITION AND ESTROGEN IN MIDDLE-AGED FEMALE MONKEYS VOYP51RR000165 

EFFECTS OF ESTROGENS AND RALOXIFENE ON COGNITION IN AGED FEMALE RHESUSMONKEYS LAC

P51RR000165 EFFECTS OF ESTROGENS ON COGNITION IN YOUNG FEMALE RHESUS LACP51RR000169 COGNITIVE FUNCTION IN THE AGED MONKEY RAPP51RR000169 TREATMENT OF OVARIECTOMIZED-INDUCED BONE LOSS IN CYNOMOLGUS MONKEYS HENP51RR000169 ESTROGEN & AGING BRAIN MORP51RR013986 ESTABLISHMENT OF AN OSTEOPENIC COLONY OF FEMALE BABOONS CARP51RR013986 A PILOT STUDY OF THE PHYSIOLOGY OF THE PERIMENOPAUSE IN BABOONS HONP51RR013986 A NONHUMAN PRIMATE MODEL OF NATURAL MENOPAUSE HONR01RR014099 NEW TECHNIQUES IN DIAGNOSING OSTEOARTHRITIS: MENOPAUSE CARR24RR016535 THE YUCATAN MICROPIG CARDIOVASCULAR MODEL OF MENOPAUSE: SOY DIET GOO

200