HIGHLIGHTS OF NIH 


WOMEN’S HEALTH AND SEX 


DIFFERENCES RESEARCH 


1990–2010
 

OFFICE OF RESEARCH ON WOMEN’S HEALTH
 

IN COLLABORATION WITH THE NIH COORDINATING 


COMMITTEE ON RESEARCH ON WOMEN’S HEALTH
 

OFFICE OF RESEARCH ON WOMEN’S HEALTH 

NATIONAL INSTITUTES OF HEALTH 

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES 
Highlights of NIH Women’s Health 

and Sex Differences Research 

1990 - 2010 

Office of Research on Women’s Health 

in Collaboration With the NIH Coordinating Committee 

on Research on Women’s Health 

Office of the Director 

National Institutes of Health 

Department of Health and Human Services 

September 2010 

NIH Publication No. 10-7606-D 

i
Acknowledgements 

Our sincere thanks to the NIH Coordinating Committee on Research on Women’s Health, 

composed of Institute and Center directors or their designees, and their Institute and Center 

colleagues. We especially want to acknowledge the extraordinary efforts of several CCRWH 

members, including Kate Nagy, M.A. (NIA), Karen Parker, Ph.D. (NCI), Mona Rowe, M.C.P. 

(NICHD), and Cora Lee Wetherington, Ph.D. (NIDA). 

ii
Introduction

As the National Institutes of Health (NIH) Office of Research on Women’s Health (ORWH) 

prepared for the events celebrating its 20th Anniversary in 2010, at which time a revised 

research agenda would be unveiled with goals and strategies for the future, it seemed 

equally important to highlight some of the progress and achievements in women’s health 

research during the years of ORWH’s existence. Looking back over so much that had been 

accomplished during these decades, as recorded in the voluminous biennial reports (see 

Appendix) that describe the totality of ORWH programs and selected highlights from the 

NIH Institutes and Centers (ICs), the information was remarkable in its scope. It was decided 

that as the strategic plan for future research was introduced, it was important to have a 

distillation of landmark studies and seminal research or programs that represent some 

of the multiple aspects of past progress in women’s health and sex differences research. 

What started as a collection of two or three brief examples from each IC was eventually expanded 

into this extensive and exciting document. This occurred because of the overwhelming and 

enthusiastic response of the ICs through the NIH internal advisory Coordinating Committee 

on Research on Women’s Health (CCRWH), composed of IC directors or their designees. 

The ORWH proudly presents this report, entitled Highlights of NIH Women’s Health and 

Sex Differences Research, 1990-2010, in which the ICs themselves have identified their best 

examples of women’s health and sex differences research. It is even more encouraging to 

note that these highlights by no means are intended as a comprehensive list, but represent 

“snapshots” of examples from the 20 years of ORWH’s existence. It should also be noted 

that woven across the report are such overarching themes as genetic and molecular research, 

clinical trials and translational studies, prevention research, global health concerns, and 

minority health and health disparities. 

Without the immediate and generous contributions and efforts of the CCRWH and their IC 

colleagues, and the extraordinary efforts of several CCRWH members, including Kate Nagy, 

M.A. (NIA), Karen Parker, Ph.D. (NCI), Mona Rowe, M.C.P. (NICHD), and Cora Lee Wetherington, 

Ph.D. (NIDA), this impressive collection of briefing highlights would not have been possible. 

The ORWH and the women’s health research community thank our partners from the NIH 

ICs; the research scientists who designed, conducted, and coordinated this research; and the 

women and men who participated in these research studies. Their contributions have and will 

move forward our knowledge about girls’ and women’s health and sex/gender factors that 

may affect the health of women and men. 

Vivian W. Pinn, M.D.

Associate Director for Research on Women’s Health, and
�

Director, Office of Research on Women’s Health, NIH
�

Lisa Begg, Dr.P.H., R.N.

Director of Research Programs, ORWH

iii
iv
 
Table of Contents
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Acknowledgements ii 

Introduction iii 

Table of Contents v 

Abbreviations vii
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NIH Coordinating Committee on Research on Women’s Health ix
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R e s e a R c h h i g h l i g h t s 

Women’s Health Resources Web Portal 1
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Infancy through Adolescence, Reproductive Years Including 

Pregnancy, the Menopausal Transition, and Old Age 2
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Infancy through Adolescence 2
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Reproductive Health of Girls and Women 3
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Fertility and Infertility 6
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Pregnancy and the Perinatal Period 9
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Maternal Health 12
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Maternal Influence on Infant and Child Health 19
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The Menopausal Transition 25
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Study of Women’s Health Across the Nation (SWAN): 

Focus on the Menopausal Transition 27
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The Women’s Health Initiative (WHI) 31
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Women Growing Older 35
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Examples of Cancer in Women 38
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Cervical Cancer 38
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Breast Cancer 38
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Genes and Other Risk Factors 38
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Breast Cancer Prevention 43
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Screening, Detection, and Diagnosis of Breast Cancer 46
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Advances in Treatment of Breast Cancer 48
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Ovarian Cancer 51
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Uterine/Endometrial Cancer 52
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Lung Cancer 53
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Chronic Diseases and Conditions in Women 54 

Diabetes 54
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Eye Disease 56
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Heart Disease 57
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v
Obesity 60
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Osteoarthritis 63
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The Osteoarthritis Initiative 65
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Osteoporosis 67
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Pain 69
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Irritable Bowel Syndrome 70
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Temporomandibular Joint Disorders 70
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Urinary Incontinence 71
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Neuroscience and Brain-Based Disorders 73
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Neuroscience and the Female Brain 73
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Sexual Differentiation of the Brain and Behavior 73
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Stroke 74
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Substance Abuse 76
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Alcohol Use and Abuse 78
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Mental Health 82
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Sex Differences in Mental Health 82
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Post-Traumatic Stress Disorder 83
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Depression 84
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Immunity, Autoimmunity, and Infectious Diseases 90
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Hepatitis 91
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H1N1 (Swine) Flu 92
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Lupus 92
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Rheumatoid Arthritis 93
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Scleroderma 94
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Sjögren’s Syndrome 95
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Urinary Tract Infections 95
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The Human Microbiome 96
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Women and HIV/AIDS 97
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Rare Diseases 103
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The Rare Diseases Clinical Research Network 103
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Genetic and Rare Diseases Information Center 106
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Scientific Conferences 106
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National Toxicology Program 109
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Genetic Determinants of Sex 110
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Additional NIH Resources 111
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NIH Office of Research on Women’s Health 111
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Women’s Health Resources Web Portal 112
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Appendix: NIH Reports on ORWH and 

NIH Support for Research on Women’s Health 113
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vi
Abbreviations

Department of Health and Human Services HHS 

National Institutes of Health NIH 

NIH Office of the Director OD 

Division of Program Coordination, Planning, and Strategic Initiatives DPCPSI 

NIH Coordinating Committee on Research on Women’s Health CCRWH 

NIH Advisory Committee on Research on Women’s Health ACRWH 

NIH INSTITUTES AND CENTERS 

National Cancer Institute NCI 

National Eye Institute NEI 

National Heart, Lung, and Blood Institute NHLBI 

National Human Genome Research Institute NHGRI 

National Institute on Aging NIA 

National Institute on Alcohol Abuse and Alcoholism NIAAA 

National Institute of Allergy and Infectious Diseases NIAID 

National Institute of Arthritis and Musculoskeletal and Skin Diseases NIAMS 

National Institute of Biomedical Imaging and Bioengineering NIBIB 

Eunice Kennedy Shriver National Institute of Child Health and Human Development NICHD 

National Institute on Deafness and Other Communication Disorders NICDCD 

National Institute of Dental and Craniofacial Research NIDCR 

National Institute of Diabetes and Digestive and Kidney Diseases NIDDK 

National Institute on Drug Abuse NIDA 

National Institute of Environmental Health Sciences NIEHS 

National Institute of General Medical Sciences NIGMS 

National Institute of Mental Health NIMH 

National Institute of Neurological Disorders and Stroke NINDS 

National Institute of Nursing Research NINR 

National Library of Medicine NLM 

Center for Information Technology CIT 

Center for Scientific Review CSR 

John E. Fogarty International Center FIC 

National Center for Complementary and Alternative Medicine NCCAM 

National Center on Minority Health and Health Disparities NCMHD 

National Center for Research Resources NCRR 

NIH Clinical Center CCRWH 

vii
NIH OD PROGRAMMATIC OFFICES 

Division of Program Coordination, Planning, and Strategic Initiatives DPCPSI 

Office of AIDS Research OAR 

Office of Behavioral and Social Sciences Research OBSSR 

Office of Disease Prevention ODP 

Office of Dietary Supplements ODS 

Office of Medical Applications of Research OMAR 

Office of Rare Diseases Research ORDR 

Office of Strategic Coordination OSC 

Office of Research on Women’s Health ORWH 

OTHER FEDERAL AGENCIES 

Department of Health and Human Services HHS 

HHS Office of the Secretary OS 

Administration for Children and Families ACF 

Administration on Aging AoA 

Agency for Healthcare Research and Quality AHRQ 

Agency for Toxic Substances and Disease Registry ATSDR 

Centers for Disease Control and Prevention CDC 

Centers for Medicare and Medicaid Services CMS 

Food and Drug Administration FDA 

Health Resources and Services Administration HRSA 

Indian Health Service IHA 

Substance Abuse and Mental Health Services Administration SAMHSA 

Department of Defense DoD 

Department of Veterans Affairs VA 

US Agency for International Development USAID 

viii
NIH Coordinating Committee on Research on Women’s Health
�

Institutes/ 

Centers Representatives 

NCI Margaret Ames, Ph.D. 

NCI Karen Parker, Ph.D. 

NEI Lisa Neuhold, Ph.D. 

NEI Natalie Kurinij, Ph.D. 

NHLBI Barbara Marzetta, S.M. 

NHLBI Susan Scolnik 

NHLBI Jacques Rossouw, M.D. 

NHGRI Sanja Basaric 

NHGRI Phyllis Frosst, Ph.D. 

NIA Kate Nagy, M.A. 

NIA Karin Kolsky 

NIAAA Svetlana Radaeva, Ph.D. 

NIAAA Diedra Roach, Ph.D. 

NIAID Tamara Lewis Johnson, 

M.B.A., M.P.H. 

NIAID Diane Adger-Johnson 

NIAMS Bernadette Tyree, Ph.D. 

NIAMS Louise Rosenbaum, Ph.D. 

NIAMS Anita Linde, M.P.P. 

NIBIB Valery Gordon, Ph.D. 

NIBIB Anthony Demsey, Ph.D. 

NIBIB Ruth Grossman, D.D.S. 

NIBIB Stacy Wallick, M.P.H. 

NICHD Mona Rowe, M.C.P. 

NICHD Estella Parrott, M.D. 

NIDCD Lana Shekim, Ph.D. 

NIDCD Lonnie L. Lisle 

NIDCR Jane Atkinson, D.D.S. 

NIDCR Ruth Nowjack-Raymer, Ph.D. 

NIDDK Eleanor Hoff, Ph.D. 

NIDDK Mary Hanlon, Ph.D. 

NIDA Cora Lee Wetherington, Ph.D. 

NIDA Samia Noursi, Ph.D. 

NIEHS Sheila Newton, Ph.D. 

Institutes/ 

Centers Representatives 

NIEHS Mary Gant 

NIGMS Paula Flicker, Ph.D. 

NIGMS Donna Krasnewich, M.D., Ph.D. 

NIMH Kathleen O’Leary, M.S.W. 

NIMH Cathy Roca, M.D. 

NINDS Linda Porter, Ph.D. 

NINDS Jodi Gilman, Ph.D. 

NINR Xenia T. Tigno, Ph.D., M.S. (Physio), 

M.S. (Epi) 

NINR Paul Cotton, Ph.D., R.D. 

NLM Gale Dutcher, M.S., M.L.S. 

CSR Denise Wiesch, Ph.D. 

CSR Elaine Sierra-Rivera 

FIC Linda Kupfer, Ph.D. 

FIC Milagros Ruiz 

NCCAM Sheila Caldwell, Ph.D. 

NCMHD Derrick Tabor, Ph.D. 

NCMHD Nathanial Stinson, M.D., Ph.D. 

NCRR Padma Maruvada, Ph.D. 

NCRR Sheila McClure, Ph.D. 

CC Deborah Dozier-Hall, M.S.W. 

CC Walter Jones, M.S. 

DPCPSI Tanya Hoodbhoy, Ph.D. 

OAR Vicki Cargill, M.D. 

OAR Gina Brown, M.D. 

OAR Anissa Brown, Ph.D. 

OBSSR Wendy Nilsen, Ph.D. 

ODS Mary Frances Picciano, Ph.D. 

(Deceased August 2010) 

OIR Joan Schwartz, Ph.D. 

OITE Debbie Cohen, M.S. 

OITE Sharon Milgram, Ph.D. 

OCPL John Burklow, M.S. 

OCPL Marin Allen, Ph.D. 

ix
x
 
R e s e a R c h h i g h l i g h t s 

Women’s Health Resources Web Portal 

The NLM Division of Specialized Information Services, Outreach and Special Populations 

Branch, has partnered with ORWH to create the Women’s Health Resources Web Portal 

(http://www.womenshealthresources.nlm.nih.gov). This portal gives researchers and consumers access to the latest information in a centralized location about significant topics in 

women’s health from scientific journals, peer-reviewed sources, NIH Institutes and Centers, 

and health news sources. 

The portal focuses on health topics and the NIH Priorities for Women’s Health to identify 

research initiatives and overarching themes. The Health Topics section is organized by disease 

or condition categories, and an A to Z index is available to provide consumers with an easy 

way to locate specific health topics. The NIH Priorities for Women’s Health section is created 

from the annual recommendations put forth by the CCRWH and ACRWH. The topics for this 

section include life span, sex/gender determinants, health disparities/differences and diversity, 

and interdisciplinary research. 

Within each section, one will find topics with links to resources which were selected based 

upon their relevance and authority for the specific topic. NLM has created specific user 

friendly strategies for these topics to ease searching within ClinicalTrials.gov and PubMed. 

Other Web resources created and maintained by NLM include AIDSinfo, American Indian 

Health, Arctic Health, Household Products Database, MedlinePlus, and NIHSeniorHealth. 

The portal is also using social media to connect with the public for health awareness 

campaigns. (NLM) 

1
Infancy through Adolescence, Reproductive Years Including 

Pregnancy, the Menopausal Transition, and Old Age 

INFANCy THROUGH ADOLESCENCE 

Newborn Screening for CMV 

A study funded by NIDCD has found that the traditional “heel stick” test is not an effective 

screening tool for congenital cytomegalovirus (CMV) infection, a leading cause of hearing 

loss in children. Researchers compared the effectiveness of a common molecular diagnostic 

technology using dried blood samples to the standard method for detecting CMV in newborns, which is labor-intensive and not conducive to a widespread screening program. 

The researchers are now assessing whether analysis of saliva samples using the same 

diagnostic technology can do a better job than dried blood spots when compared with 

the standard method. (NIDCD) 

Reference: 

Boppana SB, et al. Dried blood spot real-time polymerase chain reaction assays to screen 

newborns for congenital cytomegalovirus infection. JAMA. 2010 Apr 14;303(14):1375-82. 

Adolescent Health 

Investigators using The National Longitudinal Study of Adolescent Health (Add Health) data 

have examined gender differences in a wide variety of areas related to health, including deviance, depression, violence, victimization, relationship values, educational attainment, and 

obesity, and the factors—including genetic factors—that contribute to these domains. These 

publications have appeared in diverse journals representing the social sciences, public health, 

and criminal justice. To illustrate, a number of studies have examined linkages between 

obesity, mental health, and educational attainment. They have demonstrated clear gender 

disparities in the impact of obesity. Compared with males, female adolescents are more likely 

to overestimate their weight, are more likely to diet, and at higher body mass, are less likely 

to be nominated by their peers as a friend. Overweight and obese females are less likely to 

complete high school and as young adults have lower status attainment and more depressive 

symptoms. In contrast, obesity is unrelated to psychosocial outcomes such as mental health 

and social status among males. 

References: 

Crosnoe R, Frank KA, Mueller AS. Gender, body size, and social relations in American high 

schools. Soc Forces. 2008;86(3):1189-1216. 

Martin MA, Frisco ML, May AL. Gender and race/ethnic differences in inaccurate weight 

perceptions among U.S. adolescents. Women’s Health Issues. 2009;19(5):292-9. 

Merten MJ, Wickrama KAS, Williams AL. Adolescent obesity and young adult psychosocial 

outcomes: gender and racial differences. J Youth Adolesc. 2008;37(9):1111-22. 

2
Okunade AA, Hussey AJ, Karakus MC. Overweight adolescents and on-time high school 

graduation: racial and gender disparities. Atl Econ J. 2009;37(3):225. 

Vaughan CA, Halpern CT. Gender differences in depressive symptoms during adolescence: the 

contributions of weight-related concerns and behaviors. J Res Adolesc. 2009;20(2):389-419. 

REPRODUCTIvE HEALTH OF GIRLS AND WOMEN 

Disruption of the Female Reproductive System by the Phytoestrogen Genistein 

NIEHS research indicates the ability of genistein to disrupt female reproductive development 

and function at environmentally relevant doses. Genistein is one of several known isoflavones 

which are found in coffee and a number of plants including fava beans, soybeans, and psoralea. 

Some of these effects may not be apparent until later in life. These alterations in reproduction 

and abnormal ovarian differentiation in experimental animal models, combined with prior 

studies describing an increased incidence of uterine neoplasia following developmental 

exposure to genistein, suggest that additional studies with the human population exposed 

to high levels of phytoestrogens during development is warranted. (NIEHS) 

Reference: 

Newbold RR, Banks EP, Bullock B, Jefferson WN. Uterine adenocarcinoma in mice treated 

neonatally with genistein. Cancer Res. 2001 Jun 1;61(11):4325-8. 

Tubal Sterilization 

NICHD, in collaboration with CDC, conducted a study investigating the risk of menstrual 

anomalies following tubal sterilization. Previously, there was a lack of consensus among 

the medical community about whether tubal sterilization increased a woman’s chances of 

menstrual problems such as an irregular cycle, bleeding or spotting between periods, and 

menstrual pain. This study—the largest, most comprehensive of its kind at that time—demonstrated that women who underwent tubal sterilization were at no greater risk of menstrual 

problems than the general population up to five years after undergoing the procedure. (NICHD)

Reference:
�

Westhoff C. Tubal sterilization—safe and effective. N Engl J Med. 2000 Dec 7;343(23):1724-6.
�

Insight into the Genomics of Endometriosis 

Endometriosis is one of the most common gynecological diseases. At least 5.5 million women 

in North America alone have endometriosis, causing very painful cramps or periods, and 

affecting the quality of a woman’s life. In addition, about 30 percent to 40 percent of women 

with endometriosis are infertile, making it one of the top three causes for female infertility. 

Investigators at the NCRR-supported South Dakota Biomedical Research Infrastructure Network in the University of South Dakota, Vermilion, are studying the genomics of endometriosis 

to understand the pathology of the disease and gene expression in eutopic (internal, or inside 

the uterus) and ectopic (external, or outside the uterus) endometrium. They believe that the 

differential expression data thus obtained open new avenues for exploration of the pathology 

of endometriosis (e.g., a specific subset of inflammatory genes is upregulated). (NCRR) 

3
Finding Suggests Strategies for New Treatments for Fibroid Tumors 

NICHD researchers have shown that fibroid tumors are composed largely of abnormal collagen, a protein that doesn’t respond to reproductive hormones. This research finding suggests 

that the conventional hormone therapies used to treat fibroid tumors are unlikely to produce 

much improvement and, at best, will only temporarily relieve symptoms. The researchers 

found that fibroids are composed of collagen fibrils that are arranged in large tangles, and 

loosely packed together. The tangled collagen masses constitute most of the fibroid tumors 

and contain little other uterine tissue. Fibroid tumors also appear to secrete substances that 

promote the formation of abnormal collagen mats outside the tumors, and these abnormal collagen fibrils are not affected by reproductive hormones. For this reason, attempting 

to influence fibroids by halting the production of reproductive hormones may shrink fibroids 

slightly, but will have little other effect. CDC estimates that from 25 to 40 percent of all US 

women experience symptoms from fibroids. These include painful menstrual periods, pain 

during sexual intercourse, infertility, urinary and fecal incontinence, and bowel obstruction. 

Women with fibroids are also more likely to go into labor prematurely and to experience a 

miscarriage. Fibroids also disproportionately affect African-Americans, with one study estimating that 80 percent of African-American women are affected by the growths by age 60. 

Understanding the composition of fibroids has laid the foundation for new studies of drug 

treatments that could prevent fibroids from forming or dissolve them after they have 

formed. (NICHD) 

Reference: 

Leppert P, Baginski T, Prupas C, Catherino WH, Pletcher S, Segars JH. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril. 

2004 Oct;82(Suppl. 3):1182-7. 

Treatment Advancements for Uterine Fibroids—High-Intensity 

Focused Ultrasound 

Uterine fibroids, or uterine leiomyoma, are the most common benign tumors found in females, 

occurring in about 40 percent of women by the age of 40. While the tumors are noncancerous, they can still cause considerable pain with only a few treatment options. Current 

treatment options involve medication and various forms of surgery, including myomectomy, 

uterine artery embolization, and hysterectomy depending on the severity of the case. Hysterectomies are the only sure way to cure fibroids. Most of these treatment methods have high 

risks, including loss of fertility, heavy bleeding, ovarian failure, and radiation exposure. In fact, 

20 years ago uterine fibroids were the most common diagnosis associated with approximately 

600,000 hysterectomies performed annually. In recent years, researchers have been working 

to develop treatments for uterine fibroids that do not require invasive surgeries. Investigators 

at Brigham and Women’s Hospital have developed a magnetic resonance imaging (MRI)-

guided, high-intensity focused ultrasound method that produces a color-coded temperature 

map of the targeted tissue that distinguishes ablated tissue from surrounding normal tissue. 

The MRI guidance technique uses a high-intensity ultrasound beam to focus on the targeted 

tissue and gradually destroy it without the need for invasive surgery. This method represents a major revolution in the treatment of uterine fibroids, providing a low risk, noninvasive 

4
outpatient procedure with as little as one to two days of recovery time as compared with a 

hospital stay of three to five days and four to eight weeks of recovery time for a hysterectomy 

and myomectomy. The treatment was approved by the FDA for clinical use in 2004. (NIBIB) 

References: 

McDannold N, Tempany CM, Jolesz FA, Hynynen K. Evaluation of referenceless thermometry in MRI-guided focused ultrasound surgery of uterine fibroids. J Magn Reson Imaging. 

2008;28(4):1026-32. 

Centers for Disease Control and Prevention. Special focus: surveillance for reproductive health 

(CDC Surveillance Summaries, August 8, 1997). MMWR. 1997;46(No. SS-4). 

Nonsurgical Treatments for Uterine Leiomyomas 

The NCRR-supported Center for Women’s Health Research at Meharry Medical College has 

investigated nonsurgical treatments for uterine leiomyomas (fibroid tumors) and demonstrated that an extract of green tea, epigallocatechin gallate (EGCG), has antiproliferative 

activity against human uterine leiomyoma cells and results in shrinkage of fibroid tumors in a 

mouse model. The implications of this finding are great in that they offer a novel nonsurgical 

option for the treatment of fibroids that could preserve fertility in women and provide major 

cost savings for the health care system. (NCRR) 

Bone Density Appears to Recover After Discontinuing Use of 

Injected Contraceptive 

NICHD-supported researchers found that lower bone density appears to recover in adolescent 

females once they stop using the injected contraceptive depot medroxyprogesterone acetate 

(DMPA). Previous studies had shown that women who use DMPA, marketed as Depo-Provera, 

experience a loss of bone mineral density during the time they are using the contraceptive. 

Because women develop a large amount of their bone mass from ages 15 to 19, researchers 

were concerned that DMPA use might place adolescents at higher risk for bone fracture or 

osteoporosis later in life. The data showed, however, that after adolescents stop using DMPA, 

their bone density can increase to levels comparable to those of other women in their age 

group. About 10 percent of US female adolescents from 15 to 19 who are using birth control 

use DMPA, as compared with 3 percent of US women overall. The younger women in this study 

both lost bone density and increased bone density more rapidly than did the older women in a 

previous study. Although the potential loss of bone density is one of many considerations that 

go into a woman’s choice of contraceptive method, these studies provide reassurance that 

bone loss is regained, even in younger users. (NICHD) 

Reference: 

Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density 

among adolescent women using and discontinuing depot medroxyprogesterone acetate 

contraception. Arch Pediatr Adolesc Med. 2005;159(2):139-44. 

5
FERTILITy AND INFERTILITy 

FOXL2: A Gene That Is Critical to Sex Determination and Maintenance 

of Fertility 

Up to one percent of women experience menopause before age 40, a condition known as 

premature ovarian failure (POF). POF can occur as a result of acquired damage to the ovaries (for example, from radiation therapy, chemotherapy, or an autoimmune disorder), but 

appears to be inherited in approximately one-third of cases. In 2001, NIA and European investigators identified a gene called FOXL2 that is mutated in blepharophimosis ptosis epicanthus 

inversus syndrome, a rare condition that causes eyelid defects in newborns and is associated with POF in affected women. FOXL2 is the only gene identified to date that is uniquely 

expressed in the ovaries, and subsequent work has demonstrated that it is required both for 

ovarian follicle formation and for the determination and maintenance of female sex in the 

developing embryo. Its role in ovarian development and function suggests FOXL2 as a 

possible target for treatment of some forms of infertility. (NIA) 

References: 

Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, 

Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, 

Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G. The putative forkhead transcription 

factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. 

Nat Genet. 2001;27(2):159-66. 

Ottolenghi C, Pelosi E, Tran J, Colombino M, Douglass E, Nedorezov T, Cao A, Forabosco A, 

Schlessinger D. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to 

germ cells. Hum Mol Genet. 2007;16(23):2795-2804. 

Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W, Forabosco A, Cao A, Schlessinger D, Pilia G. Foxl2 disruption causes mouse ovarian failure by pervasive blockage 

of follicle development. Hum Mol Genet. 2004;13(11):1171-81. 

Adult Mice Continue to Produce Eggs 

One of the basic underpinnings of reproductive biology has been the tenet that the number 

of oocytes (eggs) in the ovaries of most mammals—including humans—is fixed at birth and 

declines throughout life, coinciding with a woman’s diminishing fertility as she approaches 

menopause. However, in 2004, NIH-supported researchers uncovered surprising evidence 

that egg production in mice may continue on a small scale throughout life. While additional 

research is needed, the results of this study have called into question decades of scientific 

thought. The finding that new eggs are produced into adulthood in mice may, if extended to 

humans, lead to interventions to regulate the rate at which oocytes are formed. This could, in 

turn, have important implications for the treatment of premature ovarian failure, the extension 

of fertility, or even the timing of menopause. (NIA) 

Reference: 

Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in 

the postnatal mammalian ovary. Nature. 2004(6979);428:145-50. 

6
Primary Ovarian Insufficiency 

Primary ovarian insufficiency (POI) is a condition in which the ovaries in women, generally 

younger than 40, stop functioning normally, leading to infertility and a range of symptoms 

associated with early menopause. This condition affects 1 in 100 women under the age of 40. 

A study conducted by NICHD found that the ovaries of women with POI contain immature 

eggs, adding to previous research showing that ovulation may occur in these patients. This 

important finding provides hope for developing new ways to treat the infertility that is 

generally associated with POI. (NICHD) 

Reference: 

Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N, Troendle JF, Nelson LM. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 

2009;94(7):2277-83. 

Addison’s Disease 

Researchers at NICHD demonstrated that the incidence of a life-threatening adrenal condition known as primary autoimmune adrenal insufficiency, or Addison’s disease, is more than 

300 times higher among women with primary ovarian insufficiency (POI) than among members of the general population. The risk of this adrenal condition among women with POI was 

3.2 percent, compared with an incidence of 1 in 10,000 in the general population. The study 

suggested that an adrenal antibody test would be an effective screening tool for detecting 

adrenal insufficiency in women with POI. (NICHD) 

Reference: 

Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic 

auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. 2002;17(8):2096-100. 

Prevention of Postprandial Hypoglycemia Using n-3/n-6 PUFA in PCOS 

Polycystic ovary syndrome (PCOS) affects 1 in 16 women; individuals with this condition commonly experience infertility, facial hair growth, and an increased risk for obesity, diabetes, 

and heart disease. Treatment of insulin resistance and obesity improves ovarian function and 

reduces infertility. NIH-supported investigators have demonstrated that PCOS patients frequently develop postprandial hypoglycemia (a drop in blood sugar two to four hours after 

eating), which causes sugar craving and overeating, and increases secretion of the hormones 

that lead to obesity and diabetes. Avoiding hypoglycemia may protect these patients from 

gaining additional weight and becoming diabetic. These investigators are now working to 

determine whether the essential and/or the long-chain omega (n)-3 polyunsaturated fatty 

acids (PUFAs), such as can be found in supplements including fish oil and flax seed oil, can 

prevent postprandial hypoglycemia and its unfavorable endocrine consequences in women 

with PCOS. (ODS) 

7
Women’s Fertility Is Better Understood 

Basic aspects of human fertility were not known until fairly recently. Landmark papers 

by NIEHS researchers established the window of women’s fertility in the menstrual cycle. 

Researchers showed that women are able to conceive only during six days of the menstrual 

cycle: the day of ovulation and the five days that precede it. Timing of sexual intercourse in 

relation to ovulation affects the probability of conception, survival of the pregnancy, and sex 

of the baby. If it were possible to accurately predict these six days, women could perfectly 

control their fertility through timing of intercourse alone. Unfortunately, the natural variability 

of the menstrual cycle makes these six fertile days difficult to predict. 

Furthermore, home pregnancy tests are not as trustworthy as the package inserts may suggest. 

NIEHS researchers showed that the natural variability in ovulation can produce a negative reading at the missed period even in a cycle where the woman has conceived. (NIEHS) 

References: 

Wilcox AJ, Baird DD, Dunson D, McChesney R, Weinberg CR. Natural limits of pregnancy 

testing in relation to the expected menstrual period. JAMA. 2001;286(14):1759-61. 

Wilcox AJ, Dunson D, Baird DD. The timing of the fertile window in the menstrual cycle: 

day-specific estimates from a prospective study. BMJ. 2000;321(7271):1259-62. 

Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation: 

effects on the probability of conception, survival of the pregnancy and sex of the baby. 

New Engl J Med. 1995;333(23):1517-21. 

Acupuncture May Facilitate Pregnancy Achievement in Women 

Undergoing IVF 

Research findings based on a review of seven clinical trials of acupuncture given with embryo 

transfer in women undergoing in vitro fertilization (IVF) indicate that acupuncture may 

improve rates of pregnancy. The reviewers found that acupuncture given as a complement 

to IVF increased the odds of achieving pregnancy. According to the researchers, the results 

indicate that 10 women undergoing IVF would need to be treated with acupuncture to bring 

about one additional pregnancy. The study results, which are considered preliminary, point 

to a potential complementary treatment that may improve the success of IVF and lay the 

groundwork for additional clinical trials to confirm these findings. (NCCAM) 

Reference: 

Manheimer E, Zhang G, Udoff L, Haramati A, Langenberg P, Berman BM, Bouter LM. Effect 

of acupuncture on rates of pregnancy and live birth among women undergoing In Vitro 

fertilization: systematic review and meta-analysis. BMJ. 2008;336(7643):545-9 

Improving Methods for Recovering Eggs at Earlier Stages 

For the first time, NICHD-supported researchers activated mouse egg cells at the earliest stage 

of their development and brought them to maturity. Researchers also replicated the finding 

by bringing human eggs to maturity in the laboratory. Current infertility treatment techniques 

8
stimulate immature eggs so they develop to the stage at which the eggs can be fertilized, but 

these techniques work only on eggs at a comparatively late stage of development. These laterstage eggs are few in number and much more difficult to recover than the early-stage eggs 

used by the researchers in this study. Using the new technique, the researchers brought dormant mouse eggs to full maturity within the laboratory. The eggs then were fertilized and 

transferred into female mice, which carried them to term. The human eggs were not fertilized. 

The technique is still in its early stages, has not been sufficiently studied for human use, and will 

require several more years of study. According to the researchers, this technique could one day 

be used to treat female infertility, particularly forms of infertility in which the supply of available 

eggs is diminished or limited. Similarly, the technique could be combined with efforts to bank 

the ovarian tissue of women in need of cancer therapy that might cause infertility. (NICHD) 

Development of the Hamilton Thorne ZILOS-tk Laser to Assist 

Reproduction Technologies 

The NCRR-supported Laser Microbeam and Medical Program (LAMMP) at the University of 

California at Irvine provided essential laser methods and technologies for development of the 

Hamilton Thorne ZILOS-tk Laser. This is a commercial product for laser-assisted hatching of 

human embryos in in vitro fertilization procedures, which uses a precisely focused laser beam 

as a rather gentle approach to assisted hatching. The development of laser microbeams and 

their application to gamete manipulation in assisted reproduction technologies was pioneered 

in the LAMMP facility. A description of the instrument is available at http://www.hamiltonthorne.com/products/lasers/zilostk/index.htm. (NCRR) 

PREGNANCy AND THE PERINATAL PERIOD 

An Experimental Vaccine to Protect the Fetus from a Common Virus 

The herpes virus cytomegalovirus (CMV) is quite common in the United States and, with 

important exceptions, does not cause symptoms in infected individuals. CMV infection in a 

pregnant woman, however, can infect the fetus, causing stillbirth, or in surviving infants, longterm consequences including cerebral palsy, intellectual and developmental disabilities, and/or 

hearing loss. Although CMV is treatable, there is no way to prevent it and its typically asymptomatic presentation means that it may not be detected in time during a pregnancy to prevent 

fetal infection. In a 2000 report, the Institute of Medicine identified creation of a CMV vaccine 

as a top priority and an NICHD-supported investigator has taken an important step toward 

achieving that goal. A vaccine created by the investigator significantly reduced CMV-related 

stillbirths in experimental rodents, an advance that could ultimately lead to a safe and effective CMV vaccine for humans. (NICHD) 

Reference: 

Schleiss MR, Lacayo JC. Preconceptual administration of an alphavirus replicon UL83 (pp65 

homolog) vaccine induces humoral and cellular immunity and improves pregnancy outcome 

in the guinea pig model of congenital cytomegalovirus infection. J Infect Dis. 2007 Mar 

15;195(6):789-98. 

9
Preventing Preterm Labor: Using 17-Hydroxyprogesterone 

Premature birth, which is defined as birth prior to 37 weeks of gestation, is a leading cause 

of infant morbidity and mortality. In the United States, approximately 12 percent of all births 

are premature, accounting for approximately 500,000 infants born annually. Prematurity 

also accounts for approximately 70 percent of all neonatal deaths and nearly 50 percent of 

long-term neurological problems in infants. Researchers have long sought the most effective ways to prevent preterm labor and premature births. The first such advance came with 

the discovery that 17 alpha-hyrdroxyprogesterone caproate (17P), when given to women 

who had had a previous preterm labor and were carrying a single baby, could reduce the 

risk of preterm birth by one-third. Given that the rate of twin pregnancies is increasing in the 

United States, due partly to the increase in assisted reproductive technologies, physicians 

started prescribing 17P for women carrying twins, who are also at increased likelihood of 

preterm birth. After a carefully controlled, randomized trial, researchers found that healthy 

women carrying twins who received 17P were just as likely to deliver preterm and experience 

a fetal death before 35 weeks and serious adverse fetal or neonatal events as similar women 

who received a placebo. (NICHD) 

Reference: 

Rouse DJ, et al. A trial of 17 Alpha-Hydroxyprogesterone caproate to prevent prematurity in 

twins. N Engl J Med. 2007;357(5):454-61. 

Other Promising Therapies for Delaying an Early Preterm Delivery 

Delaying a very preterm birth even by days or weeks can have profound effects on reducing neonatal mortality and morbidity. A significant percentage of preterm births that occur 

at less than 32 weeks are associated with infection. Unfortunately, medicines to slow labor or 

proactive antibiotic treatments for such conditions as bacterial vaginosis have been shown in 

previous research to be ineffective in preventing or significantly delaying delivery. Now, as a 

proof of principle using a nonhuman primate model, researchers have shown that treating the 

animal mother with both antibiotics (ampicillin) and anti-inflammatory agents (dexamethasone and indomethacin) significantly suppresses the level of inflammatory compounds in the 

amniotic fluid compared with animals who were given just an antibiotic alone or placebo. In 

addition, the combination therapy also significantly increased the interval between the time 

contractions began and the time of delivery. The findings show promise that combination 

therapy for the mother may help to prevent infection-induced preterm labor. (NICHD) 

Reference: 

Gravett MG, Adams KM, Sadowsky DW, Grosvenor AR, Witkin SS, Axthelm MK, Novy MJ. 

Immunomodulators plus antibiotics delay preterm delivery after experimental intraamniotic 

infection in a nonhuman primate model. Am J Obstet Gynecol. 2007;197(5):518.e1-8. 

10
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

New Generation of Technology Helps to Predict Preterm Labors 

About half of preterm births occur spontaneously following the premature onset of labor; 

however, two-thirds of pregnant women also experience false preterm labor—early contractions that do not result in a preterm delivery. Consequently, researchers have sought 

more effective ways to screen women in spontaneous preterm labor to allow clinicians to 

start needed treatment for those having true preterm labor and avoid unneeded treatment 

and hospitalizations for those who are simply having preterm contractions. NICHD-supported researchers developed a way to use uterine electromyography, or EMG, coupled 

with an artificial intelligence neural network computer program to analyze the resulting 

data and classify women as those simply experiencing preterm contractions versus those 

entering preterm labor. Using these new methods, 90 percent of the preterm labor women 

were correctly classified. Although such computing and new artificial intelligence technologies are just evolving, they mark the beginning of noninvasive advances that hold 

significant promise for predicting and distinguishing true from false preterm labor. Such 

advances can save unnecessary treatments for the mother and help reduce unneeded 

hospital expenditures. (NICHD) 

Reference: 

Maner WL, Garfield RE. Identification of human term and preterm labor using artificial neural 

networks on uterine electromyography data. Ann Biomed Eng. 2007;35(3):465-73. 

Artificial Placenta May Help Test Drugs During Pregnancy 

Scientists have figured out a way to grow an artificial placenta, which may help researchers learn which drugs can be given safely during pregnancy. With NIGMS funding, a team of 

researchers including physicians, biologists, and engineers was able to get “trophoblast” cells 

from a real placenta to grow in a lab chamber called a bioreactor. To create the placenta, the 

researchers first designed a nonwoven, polyethylene (DacronTM) fabric on which the placental 

cells could survive and get the proper mix of nutrients from the circulating culture fluid. The 

artificial placenta is expected to help scientists sort out which drugs are safe in pregnancy, 

since there currently is no good way to test medicines for safety and effectiveness in pregnant women. (NIGMS) 

References: 

Ma T, Yang ST, Kniss DA. Oxygen tension influences proliferation and differentiation in a tissueengineered model of placental trophoblast-like cells. Tissue Eng. 2001 Oct;7(5):495-506. 

Xie Y, Sproule T, Li Y, Powell H, Lannutti JJ, Kniss DA. Nanoscale modifications of PET 

polymer surfaces via oxygen-plasma discharge yield minimal changes in attachment and 

growth of mammalian epithelial and mesenchymal cells in vitro. J Biomed Mater Res. 2002 

Aug;61(2):234-45. 

11
Maternal Health 

Does Iron Deficiency Protect Pregnant Women From Malaria? 

Low iron intake is an important factor in the development of anemia—a major cause of morbidity and mortality in pregnant women worldwide. Consequently, iron supplementation 

has been a core component of the recommended package of prenatal health interventions 

for pregnant women. However, studies in regions with high malaria prevalence have shown 

that iron supplementation may increase the risk of malaria-related illness and deaths. NIHsupported researchers examined the relationship between iron status and risk of malaria 

in pregnant women in a high-prevalence region of northeastern Tanzania. They found that 

malaria parasitemia was less frequent in women with iron deficiency than among those with 

normal iron status. The results from this study revealed for the first time that iron deficiency 

in pregnant women may provide protection from malaria. These findings warrant examination 

of current antenatal iron supplementation guidelines in malaria-endemic regions and further 

studies to guide the optimal use of iron supplementation in these regions. (FIC) 

Reference: 

Kabyemela ER, Fried M, Kurtis JD, Mutabingwa TK, Duffy PE. Decreased susceptibility to 

Plasmodium falciparum infection in pregnant women with iron deficiency. J Infect Dis. 2008 

Jul 15;198(2):163-6. 

Decreased Immune Response during Pregnancy 

Studies showed that the hormone, estrogen, which is at higher serum levels during pregnancy, 

inhibits the response of innate immune cells to viral infection and reduces immune response 

during pregnancy. Investigators also found that levels of serum cytokines were changed in 

pregnant women, which may reduce the activity of certain immune cells. (NIAID) 

References: 

Escribese MM, Kraus T, Rhee E, Fernandez-Sesma A, López CB, Moran TM. Estrogen inhibits 

dendritic cell maturation to RNA viruses. Blood. 2008;112(12):4574-84. 

Kraus TA, Sperling RS, Engel SM, Ge L, Garrido JL, Rodriguez-Garcia M, Moran TM. Peripheral 

blood cytokine profiling during pregnancy and post-partum periods. Am J Reproduct 

Immunol. 2010 Aug 15 [Epub ahead of print]. 

Point-of-Care Ultrasound for Maternal Health 

Motherhood is often a positive and fulfilling experience but for too many women it is associated with suffering, ill-health, and even death. Every day, 1,500 women die from pregnancy 

or childbirth-related complications. Most of these deaths occur in developing countries and 

most are avoidable. In addition to the differences between countries, there are also large disparities within countries between people with high and low income and between rural and 

urban populations. One way to improve maternal health in these high-risk populations is to 

ensure skilled care before, during, and after pregnancy and childbirth. 

12
Quality care often benefits from widely used technologies such as ultrasound to diagnose 

pregnancies, determine fetal age, detect abnormalities, evaluate placenta position, and determine multiple pregnancies. In order to bridge this gap, investigators from General Electric 

Global Research are developing a portable, low-cost imaging system with diagnostic capability to serve pregnant women in areas with limited access to health care services. The Digital 

Micro-Printing (DMP) method was developed as a new technology for producing low-cost 

transducers, which are the probes that will be used in new, low-cost ultrasound imaging systems. In addition, the investigators developed management algorithms that will be integrated 

into the imaging system to facilitate rapid identification of critical situations. The development 

of portable diagnostic and monitoring devices for near-patient testing, when combined with 

suitable telehealth technologies, will empower clinicians or other providers to make decisions 

at the point of care and improve outcomes. (NIBIB) 

References: 

http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM095487.pdf 

http://www.ob-ultrasound.net/history2.html 

http://www.who.int/topics/maternal_health/en/ 

Listeria Hides from the Immune System in the Placenta 

NIAID-supported researchers discovered that the placenta is a protected niche for Listeria
�

replication, from which the bacteria seed the maternal organs. Thus, subsequent preterm 

delivery (spontaneous abortion) represents a defense mechanism for maternal survival. 

Results from this study challenge the theory that the increased incidence of listeriosis in 

pregnant women is due to maternal immunosuppression. Rather, the investigators propose a 

new model wherein attributes specific to the placenta are responsible for the pathogenesis 

of listeriosis in pregnancy. (NIAID)
�

Reference:
�

Bakardjiev AI, Theriot JA, Portnoy DA. Listeria monocytogenes traffics from maternal organs 

to the placenta and back. PLoS Pathog. 2006;2(6):e66.
�

Preeclampsia Is Associated With Proteins Produced by the Placenta 

Preeclampsia, which is often marked by a sudden increase in high blood pressure during 

pregnancy, affects 3 to 5 percent of all pregnancies. Not only can it impair the functioning 

of a mother’s liver, kidneys, or brain, but if left untreated, it can be life threatening for the 

mother. The only cure is to deliver the baby. If the birth is premature, complications such as 

blindness, learning disabilities, or death of the infant may result. A research study funded 

by NICHD, NIDDK, and NHLBI provided strong evidence that high levels of two proteins 

produced by the placenta interfere with the growth and function of blood vessels, leading 

to preeclampsia. Identification of key molecules that can lead to preeclampsia suggests 

potential targets to either treat or prevent the condition altogether. (NICHD) 

13
Reference:
�

Lindheimer MD, Umans JG. Explaining and predicting preeclampsia. N Engl J Med. 2006 Sep 

7;355(10):1056-8.
�

High Doses of Vitamins and Minerals Do Not Prevent Preeclampsia 

NICHD investigators have helped to settle a controversy over the effectiveness of high doses 

of calcium taken during pregnancy to prevent preeclampsia. The investigators combined and 

reanalyzed the data from many studies that, individually, had either reported inconclusive or 

inconsistent results. This reanalysis, the most comprehensive of its kind at the time, concluded 

that calcium supplementation during pregnancy does not confer any benefits to women who 

are at low risk of developing preeclampsia. 

Meanwhile, additional studies have confirmed that other potential “magic bullets” to reduce the 

risk of preeclampsia and other hypertensive disorders in pregnancy are also ineffective. Most 

recently, a study showed that taking significantly higher doses of vitamins C and E—about 10 

times the amount normally found in typical prenatal vitamins—does not prevent preeclampsia. 

These results are very useful for clinicians. In this case, results show that what appeared to be a 

promising treatment does not offer any clinical benefit to the mother. (NICHD) 

References: 

DerSimonian R, Levine RJ. Resolving discrepancies between a meta-analysis and a 

subsequent large controlled trial. JAMA. 1999 Aug 18;282(7):664-70. 

Roberts JN, et al. Vitamins C and E to prevent complications of pregnancy-associated 

hypertension. N Engl J Med. 2010 Apr 8;362(14):1282-91. 

Treatment with Misoprostol after Miscarriage Is Beneficial 

At least 15 percent of pregnancies result in miscarriage or pregnancy loss from natural causes 

before 20 weeks gestation. In some cases, a fetus dies in the womb; in other cases, a fetus 

may no longer be present but the woman continues to carry a placenta and amniotic sac. 

Occasionally, the uterus may fail to expel the remaining tissue naturally, leaving women at 

risk for infection. A randomized controlled trial conducted by researchers at NICHD and other 

institutions demonstrated that the drug misoprostol is an effective alternative to surgical treatment after miscarriage. Misoprostol induces labor by stimulating uterine contractions. Prior to 

this study, there was no conclusive evidence showing that misoprostol was effective and safe 

for routine use. The study gives women a less-costly alternative to surgery. In a subsequent 

study, NICHD–supported researchers found that giving the same drug provided a safe and 

inexpensive way to prevent postpartum hemorrhage, or excessive bleeding, a major killer of 

women in developing countries. (NICHD) 

References: 

Zhang J, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med. 2005 Aug 25;353(8):761-9. 

14
Derman RJ, Kodkany BS, Goudar SS, Geller SE, Naik VA, Bellad MB, Patted SS, Patel A, 

Edlavitch SA, Hartwell T, Chakraborty H, Moss N. Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial. Lancet. 

2006;368(9543):1248-53. 

“Late Preterm” Cesarean Delivery Puts Newborns at Significant Risk for 

Health Complications 

Women who have experienced a Cesarean delivery are typically offered the option of 

delivering their next child by the same method. The American College of Obstetricians and 

Gynecologists (ACOG) recommends that elective Cesarean deliveries be performed at or after 

the 39th week of pregnancy. Many elective Cesarean deliveries are performed as early as at 

37 weeks, however, even though shortening a pregnancy by even a little time is known to 

pose health risks to the infant. NICHD-supported researchers sought to better understand the 

types and severity of risks of such “late preterm” deliveries. They found that infants delivered 

by a repeat, elective Cesarean at or after 37 weeks but before 39 weeks experience problems in breathing, blood infection, and low blood sugar, and are significantly more likely than 

term infants to require neonatal intensive care. Infants born at 37 weeks are twice as likely to 

experience these problems, and even infants born in the last three days of the 38th week of 

pregnancy are 1.5 times more likely to experience adverse health effects. These findings provide strong support for the ACOG recommendation for elective Cesarean delivery only at the 

39th week of pregnancy. (NICHD) 

Reference: 

Tita ATN, Landon MB, Spong CY, et al. Timing of elective repeat Cesarean delivery at term and 

neonatal outcomes. N Engl J Med. 2009;360(2):111-20. 

Cesarean Delivery Elevates Risk of Placenta Previa, a Serious Birth 

Complication 

Cesarean deliveries occur in over one million women each year in the United States, accounting for nearly 30 percent of all births. Among the known risks of Cesarean delivery is placenta 

previa. This dangerous condition occurs when the placenta, which transfers oxygen and nutrients to the fetus, detaches from the lower part of the uterine wall and blocks the cervix. The 

condition prevents vaginal birth and carries a high risk to both mother and infant from hemorrhage. Given evidence of rising rates of Cesarean delivery, women and clinicians need to 

better understand the association between Cesarean delivery and risk for placenta previa. 

With NICHD support, investigators analyzed data in a registry of more than 70,000 Cesarean 

deliveries over a four-year period. They found that maternal morbidity was higher in women 

with placenta previa and that adverse maternal outcomes occurred progressively more commonly as the number of prior Cesarean deliveries increased. These data are important for the 

counseling of women with a history of Cesarean delivery with placenta previa and for better 

informing clinical decision-making with regard to their delivery. (NICHD) 

15
Vaginal Delivery after Caesarian Section Carries Less Risk Than 

Previously Believed 

A study conducted by NICHD found that a vaginal delivery after a prior Cesarean section carries a very low risk of complications such as uterine rupture or infection, oxygen deprivation to 

the infant brain, or infant death. The risk of such complications was found to be slightly higher 

than for a repeat Cesarean delivery, though repeat Cesarean delivery carried its own risks, 

such as infection and other complications of surgery and complications in future pregnancies, 

such as having the placenta grow into the uterine wall, potentially leading to heavy bleeding 

and surgical removal of the uterus. This research presents additional evidence for women to 

consider when deciding between a vaginal delivery and a Cesarean delivery after a previous 

Cesarean. (NICHD) 

Reference: 

Landon MB, et al. Maternal and perinatal outcomes associated with a trial of labor after prior 

Cesarean delivery. N Engl J Med. 2004 Dec 16;351(25):2581-9. 

Epidural Analgesia Does Not Increase Risk of Caesarian Section 

Further information for women to consider when planning their delivery was provided by the 

results of a review of labor records conducted by researchers at NICHD and the Tripler Army 

Medical Center. This study found that epidural analgesia administered to reduce pain during 

labor does not increase a woman’s chances of having a Cesarean delivery. This finding is in 

contrast to those previously reported. The results also indicate, however, that epidural 

analgesia prolongs labor by an average of 25 minutes. (NICHD) 

Reference: 

Zhang J. Does epidural analgesia prolong labor and increase risk of Cesarean delivery? 

A natural experiment. Am J Obstet Gynecol. 2001 Jul;185(1):128-34. 

Does EPA or DHA Prevent Depressive Symptoms in Pregnancy 

and Postpartum? 

Major depressive disorder is a significant cause of maternal morbidity during and subsequent 

to pregnancy. NIH-supported investigators are comparing the efficacy of fish oil rich in two 

different omega-3 fatty acids (EPA and DHA) in reducing the incidence and severity of 

depressive symptoms during pregnancy and postpartum. This proposal is designed to 

generate important data and hypotheses for the design and execution of future studies 

on the effects of fatty acids on mood disorders in pregnancy and postpartum and on 

infant and child development. (ODS) 

Research Advances in Postpartum Depression 

Research demonstrates that postpartum depression is a serious and debilitating disorder that 

affects up to 15 percent of new mothers. Women with depression who stop antidepressant 

treatment during pregnancy are at higher risk for relapse, and their risk of postpartum depression is significantly elevated as well. Several forms of treatment, including cognitive behavioral 

16
therapy (CBT), interpersonal psychotherapy (IPT), and medication treatment are effective in 

treating this disorder. Research continues into prevention efforts and improved service delivery of treatments based on individual needs. (NIMH) 

References: 

Cox JL, Murray D, Chapman G. A controlled study of the onset, duration and prevalence of 

postnatal depression. Br J Psychiatry. 1993 July;163(1):27-31. 

Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during 

pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 

1;295(5):499-507. Erratum in: JAMA. 2006 Jul 12;296(2):170. 

Dimidjian S, Goodman S. Nonpharmacologic intervention and prevention strategies for depression during pregnancy and the postpartum. Clin Obstet Gynecol. 2009 Sep;52(3):498-515. 

Gaynes BN, Gavin N, Meltzer-Brody S, Lohr KN, Swinson T, Gartlehner G, Brody S, Miller WC. 

Perinatal depression: prevalence, screening accuracy, and screening outcomes. Evidence 

report/technology assessment no. 119. Prepared by the RTI-University of North Carolina 

Evidence-based Practice Center, under contract no. 290-02-0016. AHRQ Publication No. 05- 

E006-2. Rockville (MD): Agency for Healthcare Research and Quality; 2005 Feb. 

O’Hara MW, Stuart S, Gorman LL, Wenzel A. Efficacy of interpersonal psychotherapy for postpartum depression. Arch Gen Psychiatry. 2000;57(11):1039-45. 

Wisner KL, Sit DK, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Jones-Ivy S, 

Bodnar LM, Singer LT. Major depression and antidepressant treatment: impact on pregnancy 

and neonatal outcomes. Am J Psychiatry. 2009 May;166(5):557-66. 

Post-Pregnancy and the Immune System 

A study found that women between four and six weeks postpartum had a significantly 

upregulated innate immune system compared with controls, as shown by higher levels of 

inflammatory cytokines and C-reactive protein, and fewer symptoms of common infectious 

illnesses. The results suggest that a new mother’s immune system may be uniquely primed to 

counteract microbial infections following pregnancy. Further work showed that postpartum 

depression may be associated with reduced immunity and that suppressed levels of natural killer cell activity, which are present during pregnancy possibly to prevent rejection of the 

fetus, continue into the postpartum period. (NINR) 

References: 

Groer MW, Davis MW, Smith K, Casey K, Kramer V, Bukovsky E. Immunity, inflammation and 

infection in post-partum breast and formula feeders. Am J Reprod Immunol. 2005;54(4):222-31. 

Groer MW, Morgan K. Immune, health and endocrine characteristics of depressed postpartum 

mothers. Psychoneuroendocrinology. 2007;32(2):133-9. 

Groer M, El-Badri N, Djeu J, Harrington M, Van Eepoel J. Suppression of natural killer cell cytotoxicity in postpartum women. Am J Reprod Immunol. 2010;63(3):209-13 

17
NIH State-of-the-Science Conference: Cesarean Delivery on Maternal 

Request, March 27–29, 2006 

NICHD and OMAR convened an independent panel in 2006 to assess the available scientific 

evidence on the growing trend of elective Cesarean delivery. The panel found that there was 

insufficient evidence to fully evaluate the benefits and risks of Cesarean delivery on maternal 

request as compared with planned vaginal delivery and more research was needed. The panel 

further concluded that: 

• Until quality evidence becomes available, any decision to perform a Cesarean 

delivery on maternal request should be carefully individualized and consistent 

with ethical principles.
�

• Given that the risks of placenta previa and placenta accreta rise with each Cesarean 

delivery, Cesarean delivery on maternal request is not recommended for women 

desiring several children. 

• Cesarean delivery on maternal request should not be performed prior to 39 weeks 

of gestation or without verification of lung maturity, because of the significant 

danger of neonatal respiratory complications. 

• Maternal request for Cesarean delivery should not be motivated by unavailability 

of effective pain management. Efforts must be made to ensure availability of pain 

management services for all women. (OMAR) 

NIH Consensus Development Conference on Vaginal Birth after Cesarean: 

New Insights, March 8–10, 2010 

OMAR worked with NICHD to convene the NIH Consensus Development Conference on 

Vaginal Birth after Cesarean (VBAC): New Insights in March 2010. A major finding of the 

Conference’s independent panel was that given the available evidence, trial of labor is a 

reasonable option for many pregnant women with one prior Cesarean delivery by low 

transverse uterine incision. The panel further recommended that the American College of 

Obstetricians and Gynecologists and the American Society of Anesthesiologists reassess 

their requirement for “immediately available” surgical and anesthesia personnel in thencurrent guidelines, to address barriers that women with a prior Cesarean delivery face in 

gaining access to clinicians and facilities that are able and willing to offer trial of labor. 

In July 2010, the American College of Obstetricians and Gynecologists issued new guidance 

on the issue that emphasizes the importance of thorough counseling on risks and benefits 

of planned repeat Cesarean delivery compared with VBAC, including discussion of measures 

that can be taken if a woman who is otherwise a good candidate for VBAC is to deliver at a 

facility that may not meet the “immediately available” standard. (OMAR) 

18
Maternal Influence on Infant and Child Health 

DHA Supplementation and Pregnancy Outcome 

Docosahexaenoic acid (DHA) is a member of the omega-3 fatty acid family; it is found in all cell 

membranes, and is accumulated in especially large quantities in the retina and brain. Over the past 

decades, evidence has accumulated in support of the hypothesis that DHA may have an important role in pregnancy health and outcome, as well as in the postnatal development of perceptual 

and cognitive function in infancy. However, prior work on this topic has focused on postnatal 

supplementation and the amelioration of risk in premature infants; this is in contrast to evidence 

indicating that DHA is accumulated in the fetal brain during gestation, probably through maternal 

dietary intake. NIH-supported investigators are now studying whether prenatal supplementation 

with DHA may lead to positive pregnancy and postnatal outcomes. In an earlier clinical trial 

conducted by this research team, a relatively low level of DHA supplementation (approximately 

100 mg/day) during the last trimester of pregnancy was associated with a longer gestation 

period and improved infant cognitive outcomes. The current trial will elucidate the effects of a 

larger dose of supplement and longer duration of supplementation, and will provide important 

information regarding the use of this popular supplement in mid- to late pregnancy. (ODS) 

Study Shows Adverse Effects of Air Pollution on Births 

A study conducted by researchers at the University of California, Los Angeles, showed that 

women who lived in regions with higher levels of air pollution—caused mainly by vehicle traffic—were approximately 10 to 25 percent more likely to have a preterm baby than women who 

lived in less-polluted areas. This was especially true for women who breathed polluted air during the first trimester or during the last months and weeks of pregnancy. Air pollution remains 

a major public health problem that affects everyone, particularly pregnant women. (NIEHS) 

Reference: 

Ritz B, Wilhelm M, Hoggatt KJ, Ghosh JK. Ambient air pollution and preterm birth in the 

environment and pregnancy outcomes study at the University of California, Los Angeles. 

Am J Epidemiol. 2007 Nov 1;166(9):1045-52. 

Periodontal Disease May Not Be a Risk Factor for Preterm Birth 

Earlier studies identified a significant association between maternal periodontal disease and 

preterm delivery (gestational age (GA) <37 weeks) and decreased fetal weight (birth weight 

(BW) <2500g). The Obstetrics and Periodontal Therapy Trial and the Maternal Oral Therapy 

to Reduce Obstetric Risk Trial found treatment of periodontal disease during pregnancy did 

not reduce the incidence of preterm birth or low birth weight. However, both studies found 

that dental treatment through the second trimester of pregnancy was safe. (NIDCR)
�

References:
�

Michalowicz BS. Treatment of periodontal disease and the risk of preterm birth. N Engl J Med. 

2006 Nov 2;355(18):1885-94.
�

Offenbacher S, et al. Effects of periodontal therapy on rate of preterm delivery: a randomized 

controlled trial. Obstet Gynecol. 2009 Sep;114(3):551-9.
�

19
Genetic Risk Factors for Preterm Birth: Danish National Birth Cohort Study 

Preterm labor resulting in the delivery of a premature infant is a complex problem with an 

enormous impact on individuals, families, and society. About 500,000 children will be born 

prematurely in the United States this year, and worldwide 5 million will die of prematurity and 

its complications. It is the single largest contributor to disability adjusted life years (DALYs), a 

measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, insufficient resources have been 

targeted to discover its underlying etiology. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition, 

and genetic factors. Numerous family and twin studies provide strong evidence that genetic 

factors underlie about 40 percent of the risk for prematurity. The single best predictor for 

preterm delivery is a previous preterm birth. A major challenge in studying genetic factors in 

prematurity is that the risk could reside either in the mother and her uterus or in the infant/ 

placenta. Thus, any approach to studying preterm birth should account for both infant and 

maternal risk, environmental covariates, and interactions. 

The Danish National Birth Cohort Study is a well-established, prospective cohort study that 

has the advantage of enrolling women early in pregnancy, when the outcome is still unknown, 

so that bias in data collection and sampling is minimized. The Danish study has followed over 

96,000 women beginning in the first trimester of pregnancy and has extensive biologic and 

epidemiologic data on the outcomes of both mother and child. In this research study, the 

team is performing a genome-wide case/control analysis using 1,000 very-well-characterized cases of spontaneous preterm birth, with biological samples on the mother and infant, 

drawn from the Danish National Birth Cohort Study. These are then matched to 1,000 mother/ 

infant controls, born at 39 or 40 weeks gestation. Extensive epidemiologic variables are used 

as covariates in the analysis. To replicate positive findings, researchers can access the deep 

resource of additional controls from the same Danish National Birth Cohort Study as well as 

more than 1,000 mother/father/preterm infant triads available from a large sample collection 

in the United States, and a further 1,000 U.S. case/controls enriched for African-Americans, a 

population known to have high rates of preterm labor. Positive results involving environmental factors can be further investigated, as the Danish cohort has maternal serum samples from 

early and mid pregnancy, as well as additional epidemiologic and outcome data. The study 

should enable a better understanding of the biology of parturition, identify common genetic 

factors that play a role in prematurity, and suggest environmental modifications that can prolong gestation, with the goal of improving both neonatal and adult outcomes. (NHGRI) 

Low Maternal Cholesterol Levels May Increase Risk of Preterm Delivery 

and Low Birth Weight 

A study published in October 2007, led by NHGRI intramural researchers, showed that pregnant women who have very low cholesterol levels might face a greater risk of delivering 

their babies prematurely. The study found that low maternal cholesterol levels, which may 

be related to a woman’s genetic makeup, diet, or other health factors, might also lead to low 

birth weight. Researchers noted a differing impact of low cholesterol levels on the rates of 

20
premature delivery in white and African-American mothers, which is of particular interest 

since premature delivery is a leading cause of health disparities. 

While most health advice warns against too much cholesterol, this study suggests dangerous 

implications from having too little cholesterol and emphasizes the importance of a moderate cholesterol intake during pregnancy. These findings give researchers renewed impetus to 

refine the understanding of cholesterol levels in pregnant women and to explore the genetic, 

nutritional, and other factors that influence maternal cholesterol. They will also lead to a better understanding of the biology of birth defects, thus suggesting more effective strategies for 

preventing them. (NHGRI) 

Genetic Variation in the Fetus: Relation to Fetal Size at Birth and 

Maternal Metabolism 

Low and high birth weights are a major cause of neonatal morbidity and mortality, and epidemiological data have established an association between birth weight and later risk of adult 

metabolic disease. Fetal growth is determined by complex interactions between fetal genes 

and the maternal uterine environment. Subtle or overt variation in maternal glucose tolerance 

which is in part genetically determined, is related to fetal size at birth. New emerging data 

suggest that genetic variation in the fetus can impact maternal metabolism. 

Given the above, an NHGRI-funded research team hypothesized that during pregnancy, geneenvironment interactions in the context of the maternal-fetal unit impact fetal size at birth and 

maternal metabolism. To address this hypothesis, the team is proposing to perform genomewide association (GWA) mapping on a subset of ~37,000 DNA samples that were collected from 

mothers and their offspring as part of the NIH-funded Hyperglycemia and Adverse Pregnancy 

Outcome (HAPO) Study. HAPO is a multicenter, international study in which high-quality phenotypic data related to fetal growth and maternal glucose metabolism have been collected from 

25,000 pregnant women of varied racial and sociodemographic backgrounds using standardized 

protocols that are uniform across centers. The team plans to genotype 1,500 infants and their 

mothers of European descent to examine the interaction between maternal genes, the intrauterine environment, and fetal genes to identify interactions that modulate genetic regulation of size 

at birth and fetal genetic variation that impacts maternal glucose tolerance. A replication study 

will be performed in additional infants and mothers of European descent with follow-up studies 

also planned in Afro-Caribbeans, Hispanics of Mexican descent, and Thais. (NHGRI) 

Common Treatment (Magnesium Sulfate) to Delay Labor Also Decreases 

Risk for Cerebral Palsy in Preterm Infants 

In the 1990s, findings from several studies seemed to suggest that magnesium sulfate, when 

given to pregnant women delivering prematurely, might help protect preterm infants from 

cerebral palsy, a condition that leaves individuals with serious lifelong disabilities. Researchers theorized that magnesium sulfate could protect against cerebral palsy by stabilizing blood 

vessels, preventing damage from oxygen depletion, and avoiding injury from swelling and 

inflammation. In recent controlled, randomized trials, researchers showed that babies born 

to women who were from 24 to 31 weeks pregnant and at risk for preterm delivery and who 

21
received intravenous magnesium sulfate, were less likely to be born with cerebral palsy than 

were preterm infants whose mothers did not receive the treatment. The magnesium sulfate, 

however, did not reduce the proportion of deaths occurring in the preterm infants. These findings have significant public health implications given that almost one-third of children with 

cerebral palsy are born preterm. (NICHD and NINDS) 

Reference: 

Rouse DJ, et al. A randomized, controlled trial of magnesium sulfate for the prevention of 

cerebral palsy. N Engl J Med. 2008 Aug 28;359(9):895-905. 

Folic Acid Supplements Reduce Babies’ Risk of Facial Clefts 

A new study finds that women who take folic acid supplements early in their pregnancies can 

substantially reduce their babies’ chances of being born with facial clefts. Researchers found 

that 0.4 mg a day of folic acid reduced by one-third the baby’s risk of isolated cleft lip (with 

or without cleft palate). Folic acid is a B vitamin found in leafy vegetables, citrus fruits, beans, 

and whole grains. It can also be taken as a vitamin supplement and is added to flour and other 

fortified foods. (NIEHS) 

Reference: 

Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, Vindenes H, Vollset SE, 

Drevon CA. Folic acid supplements and risk of facial clefts: national population-based casecontrol study. BMJ. 2007 Mar 3;334(7591):464 

Anti-Seizure Drugs and Birth Defects 

A finding supported by NINDS showed that anti-seizure drugs taken by pregnant mothers, rather than epilepsy seizures themselves, were the cause of higher-than-normal rates of 

birth defects in their babies. It has long been recognized that anti-seizure drugs contribute to 

the higher birth defect rate among epileptic mothers; however, seizure activity was believed 

to be a major contributor. The new study found that when pregnant women stopped taking 

anti-seizure drugs, they were no more likely than other women to have children with 

birth defects. This finding emphasizes that additional research is needed to find more 

and safer drug choices for pregnant epileptic women. (NINDS) 

Reference: 

Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, Ryan LM. 

The teratogenicity of anticonvulsant drugs. New Engl J Med. 2001 Apr 12;344(15):1132-8.
�

The Antiepileptic Drug Valproate Increases Risk of Birth Defects 

An NINDS-funded study examined the occurrence of birth defects and fetal death with four 

common epilepsy drugs: valproate, phenytoin, carbamazepine, and lamotrigine. Valproate 

posed the highest risk to the fetus, with over 20 percent of the pregnancies exposed to valproate 

resulting in death or birth defects such as skull and limb deformities and brain, heart, and lung 

problems. The study’s findings are consistent with those of several other recent studies and 

suggest that women with epilepsy should avoid using valproate during pregnancy. (NINDS) 

22
Reference:
�

Meador KJ, et al. In utero antiepileptic drug exposure: fetal death and malformations. 

Neurology. 2006;67(3):407-12.
�

New Research Suggests Link between Maternal Diet and Childhood 

Leukemia Risk 

A new study suggests that eating more vegetables, fruits, and protein before pregnancy may 

lower the risk of having a child who develops leukemia, the most common childhood cancer in 

the United States. Additionally, the study found that some protein sources, such as beef and 

beans, also proved beneficial in reducing risk of childhood leukemia. The researchers looked 

further and found that glutathione was the nutrient in the protein group with a strong link to 

lower cancer risk. (NIEHS) 

References: 

Jensen CD, Block G, Buffler P, Ma X, Selvin S, Month S. Maternal dietary risk factors 

in childhood acute lymphoblastic leukemia (United States). Cancer Causes Control. 2004 

Aug;15(6):559-70. 

http://www.niehs.nih.gov/news/releases/news-archive/2004/matdiet.cfm 

Improving Maternal-Child Outcomes through the Nurse-Family Partnership 

Thirty years of research on nurse home visitation for prenatal and postpartum women, as a 

means of enhancing the health and well-being of socially disadvantaged women and their 

first-born children, has shown that supporting mothers is an effective strategy for improving 

parent and child outcomes. One study examined whether the Nurse Family Partnership (NFP) 

reduced mothers’ vulnerability to the effects of stressful life events several years after the program was completed. Data from a randomized trial of the NFP were examined for 324 mothers 

who were generally low-income, young, and unmarried at the time of the birth of their first 

child. Structured interviews done 15 years after the program began showed that experiencing uncontrollable stressful life events, such as the death of a loved one, led to fewer negative 

outcomes (fewer mental health problems, less binge drinking, and better parenting practices) among nurse-visited mothers than among mothers receiving no visitation. Furthermore, 

the program’s effect on reducing vulnerability to the negative impact of life events was particularly evident among parents who were younger or had a lower sense of personal control 

at intake. These findings suggest that in addition to preventing the occurrence of the negative outcomes that were direct targets of the intervention, the NFP more generally enhanced 

mothers’ ability to cope with future stressful life events. Funding for this study was provided 

by NINR, NIMH, and other sources. (OBBSR) 

Reference: 

Izzo CV, Eckenrode JJ, Smith EG, Henderson CR, Cole R, Kitzman H, Olds DL. Reducing the 

impact of uncontrollable stressful life events through a program of nurse home visitation for 

new parents. Prev Sci. 2005 Dec;6(4):269-74. 

23
Improving Child Outcomes with Cash Incentives to Mother 

Mexico’s conditional cash transfer program, Oportunidades, was started to improve the lives of 

low-income children by providing mothers cash incentives for meeting health, nutrition, and 

educational targets in the children. From April 1998 to October 1999, low-income communities 

were randomly assigned to be enrolled in Oportunidades immediately (early treatment, n=320) 

or 18 months later (late treatment, n=186). When children were ages 8-10 years, they were 

assessed for outcomes including physical growth, cognitive and language development, and 

socioemotional development to investigate outcomes associated with participating an additional 18 months in the program. Early enrollment reduced behavioral problems for children in 

the early versus late treatment group. For all other outcomes, the two groups showed comparable benefit, except for those children whose mothers lacked formal education. Overall, children 

in the Oportunidades program improved significantly more on height, weight, language, and 

behavior than the children not enrolled in the program. These findings show that an additional 

18 months in the Oportunidades program have independent beneficial effects other than just 

providing additional money to low-income families, especially for children of women with no 

formal education. Funding for this study was provided by NICHD, FIC, the Mexican Ministry of 

Social Development, and others. (OBSSR) 

Reference: 

Fernald LC, Gertler PJ, Neufeld LM. 10-year effect of Oportunidades, Mexico’s conditional cash 

transfer programme, on child growth, cognition, language, and behaviour: a longitudinal follow-up study. Lancet. 2009 Dec 12;374(9706):1952-3. 

Breastfeeding Saves Lives 

NIEHS-funded research suggests that breastfeeding can reduce the risk of death for infants 

in their first year of life. Looking at infants between 28 days and 1 year of age, researchers 

concluded that promoting breastfeeding can potentially prevent nearly 1,000 postneonatal deaths in the United States each year. Children who were breastfed had 20 percent lower 

risk of dying between 28 days and 1 year of age than children who were not breastfed. Longer breastfeeding was associated with lower risk. The effect was the same in both black and 

white children. (NIEHS) 

References: 

Chen A, Rogan WJ. Breastfeeding and the risk of postneonatal death in the United States. 

Pediatrics. 2004 May;113(5):e435-9. 

http://www.niehs.nih.gov/news/releases/news-archive/2004/infmort.cfm 

24
THE MENOPAUSAL TRANSITION 

Defining the Stages and Symptoms of the Menopausal Transition—the Seattle 

Midlife Women’s Health Study 

This longitudinal study produced a number of important findings regarding the changes that 

midlife women encounter as they progress through the menopausal transition, including changes 

in symptoms, hormone levels, stress, and use of health services. Findings included the identification of three predictable stages in reproductive aging; in particular, an early, middle, and late 

stage of the menopausal transition. In addition, the study defined clusters of symptoms that occur 

during the transition. The symptoms, including hot flashes, sleep disruptions, and depressed 

mood, appear to be interrelated, which suggests that clinicians should use caution in designing 

treatment approaches to avoid exacerbating one symptom when treating another. (NINR) 

References: 

Mitchell ES, Woods NF, Mariella A. Three stages of the menopausal transition from the Seattle 

Midlife Women’s Health Study: toward a more precise definition. Menopause. 2000;7(5):334-49. 

Cray L, Woods NF, Mitchell ES. Symptom clusters during the late menopausal transition stage: 

observations from the Seattle Midlife Women’s Health Study. Menopause. 2010 Jul 9 [Epub 

ahead of print]. 

Tai Chi May Help Postmenopausal Women Maintain Bone Mineral Density 

NCCAM-funded researchers completed a systematic literature review that suggested Tai 

Chi may be a safe, effective, and practical alternative to conventional exercise for maintaining bone mineral density in postmenopausal women. Moreover, Tai Chi may improve balance, 

reduce the frequency of falls, and increase musculoskeletal strength. (NCCAM)
�

Reference: 

Wayne PM, Kiel DP, Krebs DE, Davis RB, Savetsky-German J, Connelly M, Buring JE. The effects 

of Tai Chi on bone mineral density in postmenopausal women: a systematic review. Arch Phys 

Med Rehabil. 2007 May;88(5):673-80. 

Black Cohosh and Hot Flashes: The HALT Study 

The Herbal Alternatives (HALT) for Menopause Study found that the herbal supplement black 

cohosh, whether used alone or with other botanicals, did not relieve hot flashes in women. 

HALT, cofunded by NCCAM and NIA, did find that women using menopausal hormone therapy 

received significant relief from their hot flashes and night sweats. (NCCAM) 

Reference: 

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor 

symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006 Dec 19;145(12):869-79. 

25
Botanical Dietary Supplements for Women’s Health 

The University of Illinois at Chicago/NIH Center for Botanical Dietary Supplements Research 

was established in 1999 to address issues of standardization, quality, safety, and efficacy of 

botanical dietary supplements. Using a multidisciplinary strategy, the Center studies botanicals with potential benefits for women’s health, focusing on plants that are reported to 

alleviate the symptoms of menopause and premenstrual syndrome. Botanical extracts are 

subjected to rigorous chemical evaluation, followed by both in vitro and in vivo biological 

testing. Standardized botanical extracts that appear efficacious and demonstrate adequate 

safety profiles in in vitro and animal models then become candidates for clinical Phase I 

trials. Research conducted by Center investigators is greatly enhancing our understanding 

of the mechanism of action of botanicals and whether they are safe and efficacious for 

women’s health. (ODS) 

NIH State-of-the-Science Conference on Management of Menopause-Related 

Symptoms, March 21-23, 2005 

The NIH State-of-the-Science Conference on Management of Menopause-Related Symptoms, held in early 2005, was convened to assess the available scientific evidence to help 

women make informed decisions about use of hormonal therapy and other strategies to 

manage troubling symptoms during the menopausal transition, especially in light of findings 

regarding important risks discovered through the Women’s Health Initiative. The Conference’s independent panel found that there are many potential alternatives to estrogen, 

but their effectiveness and long-term safety need to be studied in rigorous clinical trials in 

diverse populations of women. The panel further concluded that menopause is “medicalized” in contemporary U.S. society, and highlighted a great need to develop and disseminate 

information that emphasizes menopause as a normal, healthy phase of women’s lives. The 

panel advocated that medical care and future clinical trials be focused on women with the 

most severe and prolonged symptoms and that any barriers to professional care for these 

women should be removed. (OMAR) 

26
Study of Women’s Health Across the Nation 

(SWAN): Focus on the Menopausal Transition 

Menopause—the cessation of menstruation, signaling the end of a woman’s reproductive 

capability—is a universal aspect of aging among women. However, as recently as 20 years 

ago, scientists knew remarkably little about how women navigated the menopausal transition. At the time, our knowledge of menopause and the menopausal transition was largely 

derived from women—a majority of whom were of Northern European ancestry—who visited 

their doctors for relief of particularly bothersome symptoms. Were these women’s menopausal symptoms typical? Did women of different racial and ethnic backgrounds experience 

the menopausal transition differently? What constituted a “normal” menopausal transition? 

The answers to these questions were unknown. 

In 1994, the Study of Women’s Health Across the Nation set out to answer some of those 

questions. SWAN is the first major longitudinal study of the biological, behavioral, and psychosocial changes that occur in women as they transition from pre- to postmenopause. 

Approximately 3,300 women have participated in SWAN since its inception. An important 

aspect of the study is the multiethnic composition of the study population; SWAN includes 

white, African-American, Hispanic, Chinese, and Japanese women, so for the first time scientists have been able to identify and explore differences among women of different racial and 

ethnic backgrounds. 

SWAN’s Goals 

The specific aims of SWAN are to gain a more comprehensive understanding of menopause 

in a cohort of socially and culturally diverse women, and to: 

• Describe the symptoms, hormonal changes, and bleeding patterns of the 

menopausal transition
�

• Relate personality and behaviors, including lifestyle behaviors and use of 

menopausal hormone therapy, to age at onset, duration, symptoms, and physical 

changes of the menopause transition 

• Differentiate menopause-related changes from age-related changes at midlife 

• Elucidate the role of menopause in the development of the chronic diseases of 

aging (osteoporosis, type II diabetes, cardiovascular disease, osteoarthritis, etc.) 

• Understand cultural and ethnic differences among women with respect to midlife 

aging and the menopausal transition. 

27
What We Have Learned 

Over its 16-year history, SWAN investigators have published over 200 scientific papers 

describing important—and sometimes surprising—discoveries. The investigators have identified specific racial and ethnic differences with regard to several aspects of the menopausal 

transition. Among other differences, Japanese women as a group go through menopause 

somewhat later than Caucasian or African-American women, and levels of several key hormones may differ by race. SWAN investigators have also found that body mass index has a 

profound effect on hormone levels and perimenopausal symptoms. For example, although 

conventional wisdom once held that women with higher body fat had fewer vasomotor 

symptoms (e.g., hot flashes), SWAN investigators have found that heavier women are actually 

more likely to report these symptoms. And SWAN investigators have confirmed that women 

going through perimenopause are more likely than premenopausal or postmenopausal 

women to experience depressive symptoms and certain forms of cognitive change, but 

that these symptoms often resolve after menopause. 

Additional examples of findings from SWAN include: 

• Age at menopause. The median age at natural menopause among women in the 

study was 51.4 years, although a number of factors, including smoking, marital status, 

education, past pregnancies, and race/ethnicity influence age at menopause. 

• Changing hormone levels. Hormone profiles differ among ethnic groups, but these 

differences are highly influenced by body size. In fact, some ethnic differences in 

reproductive hormone concentrations may be explained by relative body size—a 

finding with enormous implications, given the global epidemic of obesity. 

• Perimenopausal symptoms. Caucasian women are more likely to report symptoms 

such as hot flashes and night sweats than their Asian counterparts, but are less likely 

than African-American women to report these symptoms. 

• Urinary incontinence. About half of all midlife women report some level of urinary 

incontinence. SWAN investigators have elucidated a number of risk factors for midlife 

incontinence, including worsening anxiety, high body mass index, weight gain, and 

new-onset diabetes. 

• Sleep. Sleep disturbances are common among midlife women, and SWAN 

investigators have found that they are associated with hot flashes and changes 

in the levels of certain hormones.
�

• Weight gain. Weight gain has long been observed to occur in conjunction with the 

menopausal transition, but studies prior to SWAN have concluded that weight gain 

is driven primarily by age. SWAN has been able to identify specific aspects of the 

transition that contribute to weight gain over and above age, including higher 

levels of androgens, lower levels of sex hormone-binding globulin (SHBG), surgical 

menopause (i.e., menopause brought on by surgical removal of the uterus and/or 

ovaries), and early menopausal hormone therapy use—all key factors associated 

with the development of obesity and/or severe obesity. 

28
• Cardiovascular risk factors. A longstanding hypothesis is that the menopausal transition 

sets the stage for later increased risk for heart disease. SWAN is providing fresh insights 

into exactly how the menopausal transition affects women’s risk. It appears that a sharp 

rise in LDL and total cholesterol in the year before and after the final menstrual period, 

compared with comparable periods of time earlier or later, may be associated with 

increased risk of cardiovascular disease. 

• Cognitive function. During perimenopause, SWAN participants were not able to learn 

as well as they had during premenopause. However, learning abilities rebounded to 

premenopausal levels when women became postmenopausal. The investigators also 

found that depressive symptoms and/or anxiety, sleep disturbance, and vasomotor 

symptoms did not account for this decline in cognitive performance. The investigators 

are continuing to pursue explanations for this phenomenon. 

• Bone loss and osteoporosis. Age-related bone loss appears to be minimal in most preand early perimenopausal women but accelerates dramatically in late perimenopausal 

women. Rates of bone loss were considerably slower in women in the highest third of 

body weight. Although racial differences in rates of bone loss were evident in preliminary 

analyses, these differences disappeared when the data were adjusted for differences in 

body weight. 

• Genetic factors. SWAN investigators have identified genetic variations related to daily 

sex hormone levels across the menstrual cycle as well as measures of bone mineral 

density, glucose levels and diabetes, cognition, lipids, circulating sex hormone levels, 

and hormone metabolites. Racial and ethnic differences that are correlated with these 

variations have also been identified. 

• Functional limitations. About 10 percent of women reported substantial functional 

limitations (difficulties in climbing a flight of stairs, walking a block, or bathing/dressing themselves) by midlife, while another 10 percent of midlife women reported at least 

some degree of functional limitation. Surgical menopause and use of menopausal hormone therapy were more common in the women who reported physical limitations 

than in those who did not. 

Future Directions 

As the original group of women who have participated in SWAN passes through the transition 

into their postmenopausal years, the study will continue to generate a wealth of information about how women age in America. Now in its fourth wave of funding, SWAN will move 

from being a study of menopause to a study of aging in women. The study has begun to identify longitudinal patterns of health-related characteristics likely to have an impact on women’s 

transition into older age, and will extend observation of the participants to incorporate additional cardiovascular, musculoskeletal, mental health, and quality-of-life outcomes. 

This groundbreaking study is expected to advance the understanding of how modifiable risk 

factors related to the menopause transition are linked to health outcomes later in life. These 

findings may in turn lead to improved strategies for prevention of disease and maintenance of 

robust health in older women. 

29
Funding for SWAN has been provided by NIA, NHLBI, NICHD, NIMH, NINR, NCCAM, and 

ORWH. (NIA) 

Reference: 

http://www.swanstudy.org/publications.asp 

Exploring Genetic Variation and the Menopausal Transition—SWAN: 

A series of 13 articles published from the Study of Women’s Health Across the Nation 

(SWAN) site at the University of Michigan highlighted the importance of genetic variation in 

women’s health using as examples single nucleotide polymorphisms (SNPs) from six genes 

in the sex steroid pathway. Twenty-six SNPs were found to be related to daily sex hormone 

levels across the menstrual cycle as well as measures of bone mineral density, glucose levels and diabetes, cognition, lipids, circulating sex hormone levels, and hormone metabolites. 

Further, the studies demonstrated that significant racial/ethnic differences exist in allele 

frequency and these differences appear to be associated with health outcomes. (NINR) 

Reference: 

A special supplement to the American Journal of Medicine (Volume 119S, Issue 9A, Pages 

S1-S102, September 2006) included 13 articles on the SWAN project. 

Dietary and Serum Phytoestrogens and Women’s Health Conditions 

in Midlife 

Rates of some estrogen-associated diseases, such as breast cancer, and hip fracture are 

lower in regions where diets high in phytoestrogens are consumed. However, there have 

been few studies measuring phytoestrogen exposures relative to these outcomes. An 

NIH-supported study will use data from the Study of Women’s Health Across the Nation 

(SWAN) to explore the relations between plant estrogen consumption and four outcomes 

that are important to the health of women: bone density, hot flashes, urinary incontinence, 

and cognitive performance. This study will serve as a translational research step, either 

encouraging or dissuading the future development of plant estrogen-based interventions 

for the treatment of conditions (e.g., hot flashes) or the maintenance of health (e.g., bone 

density preservation). (ODS) 

30
The Women’s Health Initiative (WHI) 

The Women’s Health Initiative is a long-term national health study that focuses on strategies 

for preventing heart disease, breast and colorectal cancer, and fracture in postmenopausal 

women. The first participants were enrolled in 1993, two years after then-NIH Director Dr. 

Bernadine Healy announced the program. WHI represents the most definitive, far-reaching program of research on women’s health ever undertaken in the United States. More than 

191,000 women of diverse race and ethnicity aged 50-79 were enrolled at 40 clinical centers 

across the country. The women agreed to participate in one or more of three clinical trials or 

an observational study, and follow-up has continued to date—for up to 17 years in the case of 

the earliest participants. 

The WHI hormone trial is a landmark study that has changed medical practice. It included two 

randomized clinical trials of postmenopausal hormone therapy (MHT)—a study of estrogen 

plus progestin in women who had an intact uterus, and a study of estrogen alone in women 

who had undergone a hysterectomy. Both were designed to test the hypothesis that longterm use of hormone therapy could reduce risk of coronary heart disease (CHD). Contrary to 

the universal recommendation at the time that postmenopausal women at any age should be 

encouraged to take hormone therapy to prevent coronary heart disease, the trial findings were 

the opposite. In fact, the combination of oral estrogen and progestin was so adverse for coronary heart disease, stroke, blood clots in the legs and lungs, and breast cancer that the trial 

was halted ahead of schedule in July 2002 to protect participants from further harm and to 

inform the general public. Although the women taking hormones had a lower incidence of 

colon cancer and fewer hip fractures, the overall balance of risks and benefits was unfavorable. 

Because it overturned conventional wisdom, the 2002 publication of the trial findings received 

widespread publicity. More importantly, these findings led to the FDA mandating a “black box” 

warning on package inserts that postmenopausal hormone therapy should not be used for 

prevention of cardiovascular disease, changes in the recommendations of professional bodies, 

and a two-thirds reduction in prescriptions for hormone therapy. 

In March 2004, the estrogen-alone trial also was halted ahead of schedule. After an average 

of nearly 7 years of treatment, estrogen therapy had no effect on CHD risk, but increased risk 

of stroke and blood clots in the legs. Unlike estrogen plus progestin, estrogen alone did not 

increase the risk of breast cancer, and a favorable effect on bone health emerged. Both types 

of hormone therapy increased the risk of memory problems and dementia, again contrary to 

expectation. On balance, however, the trial indicated that postmenopausal hormone therapy 

should not be prescribed for chronic disease prevention. 

Follow-up studies and data analyses, and investigations using biological samples and clinical 

data from WHI participants, are ongoing and continue to generate many publications on 

a wide variety of women’s health issues. 

31
• The impact of these findings is illustrated by the national reduction in breast cancer incidence following 2002, in parallel with the reduction in hormone prescriptions. This 

phenomenon was confirmed in follow-up studies within WHI showing similar reductions in breast cancer risk after participants stopped taking estrogen plus progestin, and 

this reduction was not due to any change in the frequency of mammograms. The risk of 

blood clots also diminished, as did the benefit for hip fractures. Continued analyses of 

the WHI trials indicated that the excess risk of coronary heart disease was concentrated 

in older women, and particularly those with persistent hot flashes or night sweats (however, the increased risks of strokes and blood clots were independent of age). The finding 

that overall health risks due to short-term hormone therapy are less marked in younger women is important, because the current recommendations are that hormone therapy 

primarily be used in the short term for relief of hot flashes and night sweats. 

• The WHI trial of low-fat dietary pattern (published in 2006) showed a nonsignificant reduction in breast cancer overall, but a significant reduction in the subset of women who 

started at the highest levels of fat intake. This is consistent with the public health message to avoid high-fat diets. Interestingly, a low-fat diet is also a high-carbohydrate diet, 

and in spite of consuming a high-carbohydrate diet the participants lost rather than 

gained weight, and had a slightly reduced risk of diabetes. 

• The trial of calcium and vitamin D, also published in 2006, showed no overall benefit for 

fractures, but there was evidence of improvement in bone mineral density compared 

with placebo, and hip fractures were reduced in women over age 60. Again, these findings are consistent with the public health message of maintaining an adequate intake of 

calcium and vitamin D. 

• The observational study has yielded important findings, such as the fact that even moderate regular exercise such as walking is associated with reduced risk of breast cancer 

and cardiovascular disease. 

• These and other contributions of the program were celebrated at The WHI Legacy to 

Future Generations of Women, a conference on the past, present, and future of WHI, 

held February 28 - March 1, 2006 at NIH and cosponsored by NHLBI and ORWH. 

The WHI program will continue until at least 2015; during this next phase the study will 

address the causes of cardiovascular conditions in older women (including heart failure, atrial 

fibrillation, and valvular heart disease in addition to coronary heart disease, peripheral arterial 

disease, and stroke) and conversely what determines healthy aging, including the absence of 

cardiovascular disease. The WHI is uniquely suited to study the important health demographic 

of older women since it has very large numbers of older women (one-third of participants are 

now over age 80). The program will intensify its efforts to mentor new investigators and serve 

as a resource for studies of the causes and mechanisms of disease including genomic, epigenetic, proteomic, and metabolomic studies using the stored bloods. (NHLBI) 

References: 

Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen 

plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-33. 

32
http://www.nhlbi.nih.gov/whi/references.htm 

Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA. 2004;291(14):1701-12. 

Hormone Therapy and the Brain: A Question of Timing? 

Postmenopausal women have a higher risk of developing Alzheimer’s disease (AD) than do 

men, and some studies have suggested that the drop in estrogen levels post menopause may 

be a factor. Estrogen has been shown to have neuroprotective effects in laboratory studies, 

and results of some population studies have suggested that use of menopausal hormone 

therapy (MHT) may be associated with a reduced risk of cognitive decline and dementia. 

However, other studies have not shown such an association. 

NIH has supported or been a part of several major studies of MHT’s effects on cognitive 

health. For example: 

• The Women’s Health Initiative Memory Study (WHIMS), an ancillary study to the 

Women’s Health Initiative clinical trials of MHT, tested the hypothesis that MHT protects 

against dementia and global cognitive decline in women age 65 and older. Contrary to 

expectation, WHIMS showed that MHT increased the risk for probable dementia and 

resulted in poorer global cognition over time. 

• In the WHIMS-MRI study, a subgroup of WHIMS participants underwent magnetic resonance imaging of the brain in an attempt to determine the reason for the unexpected 

MHT-associated increase in risk for dementia. The investigators found that women who 

had received MHT as part of the study had smaller brain volumes in areas important in 

maintenance of normal memory function, but similar volumes of tissue showing abnormal vascular changes, when compared with women who had received a placebo. 

• The Women’s Health Initiative Study of Cognitive Aging (WHISCA) was an ancillary 

study to WHIMS to determine whether postmenopausal MHT influenced age-related 

change in memory and other specific cognitive functions in older women without 

dementia. Once again contrary to prediction, MHT had, at best, no effect on cognitive 

function, although one regimen (combination estrogen plus progestin) was associated 

with greater verbal memory decline over time compared with placebo. 

• Most recently, in the Prevention of Postmenopausal Alzheimer Disease and Cognitive 

Loss with Replacement Estrogen (PREPARE) trial, women ages 65 and older with a 

family history of dementia were randomized to receive MHT or placebo. The medication 

was discontinued following reports from WHIMS, but investigators continued to follow 

the participants. The investigators found that according to predefined criteria on cognitive testing, there was significantly more worsening of cognitive function from baseline 

in the MHT group, and the composite memory score in the treatment group was significantly lower than in the placebo group at the first two annual follow-ups, with no 

differences noted in the subsequent three years. 

33
These results demonstrate that use of certain forms of menopausal hormone therapy is 

associated with an increased risk of cognitive decline and dementia in older women. However, a majority of the participants in these studies were over age 65—a decade or more 

past the menopausal transition. Other research has suggested that when used at younger 

ages (i.e., around perimenopause), MHT may have a protective effect on the brain. Ongoing NIH-supported studies, including the Kronos Early Estrogen Protection Study/Cognitive 

and Affective Study (KEEPS/CA), are focused on determining whether a “window of opportunity” for optimal timing of MHT with regard to cognition may exist, and whether women 

experiencing significant perimenopausal symptoms may use MHT without risk of adverse 

cognitive effects. (NIA) 

References: 

WHIMS: 

Espeland MA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004;291(24):2959-68. 

Shumaker SA, et al. Conjugated equine estrogens and incidence of probable dementia and 

mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory 

Study. JAMA. 2004;291(24):2947-58 

WHIMS-MRI: 

Coker LH, Hogan PE, Bryan NR, Kuller LH, Margolis KL, Bettermann K, Wallace RB, Lao Z, 

Freeman R, Stefanick ML, Shumaker SA. Postmenopausal hormone therapy and subclinical 

cerebrovascular disease: the WHIMS-MRI Study. Neurology. 2009;72(2):125-34. 

Resnick SM, Espeland MA, Jaramillo SA, Hirsch C, Stefanick ML, Murray AM, Ockene J, 

Davatzikos C. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI 

Study Neurology. 2009;72(2):125-34. 

WHISCA: 

Resnick SM, et al. Effects of combination estrogen plus progestin hormone treatment on 

cognition and affect. J Clin Endocrinol Metab. 2006;91(5):1802-10. 

Resnick SM, et al. Effects of conjugated equine estrogens on cognition and affect in postmenopausal women with prior hysterectomy. J Clin Endocrinol Metab. 2009;94(11):4152-61. 

PREPARE: 

Sano M, Jacobs D, Andrews H, Bell K, Graff-Radford N, Lucas J, Rabins P, Bolla K, Tsai WY, 

Cross P, Andrews K, Costa R, Xiaodong Luo. A multi-center, randomized, double blind placebocontrolled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: 

design and baseline characteristics. Clin Trials. 2008;5(5):523-33. 

Sano M, et al. Prevention of Postmenopausal Alzheimer Disease And Cognitive Loss With 

Replacement Estrogen (PREPARE) Study Results. Presented at the International Conference 

on Alzheimer’s Disease; 2010 Jul 14; Honolulu, Hawaii. 

KEEPS: 

http://www.keepstudy.org/index.cfm 

WHI has been funded by NHLBI with additional funding for WHIMS provided by NIA. 

34
WOMEN GROWING OLDER
�

Pelvic Organ Prolapse and Urinary Incontinence 

Pelvic organ prolapse is a condition in which the pelvic muscles and connective tissue of 

the pelvic cavity are weakened or damaged. Lack of support allows the uterus, bladder, 

and bowel to press on the vagina, which may cause it to invert, and the organs may protrude through the vaginal opening. In some cases this can lead to chronic pain, surgery, 

and greatly diminished quality of life. Previously, surgery to correct pelvic organ prolapse 

involved only a single procedure, and a second surgery would be performed only if incontinence developed. Research conducted by the NICHD Pelvic Floor Disorders Research 

Network found that the incidence of incontinence was reduced by half when two procedures 

were performed during the same operation. A more effective surgical approach could benefit the more than 200,000 women who undergo prolapse surgery each year in addition to 

reducing health care costs. 

Another urinary issue that may be treated surgically is stress urinary incontinence. This is a 

common condition in which activities such as coughing, laughing, and sneezing cause leakage of urine. In some cases this can be bothersome; in others, it is extremely debilitating. The 

results of a recent comparative effectiveness trial supported by NICHD, NIDDK, and ORWH 

suggest that two common, minimally invasive surgeries for stress urinary incontinence, known 

as midurethral-sling surgeries, are equally effective treatments. However, the two procedures 

were found to have different side effects. This information may help women to weigh the 

benefits and risks of surgical options to treat stress urinary incontinence. 

Some women may wish to explore nonsurgical approaches to treating urinary incontinence. 

Research supported by NICHD found that weight loss of 5 to 10 percent was as effective as 

other nonsurgical treatments in correcting urinary incontinence among overweight and obese 

women. The authors of the study concluded that weight loss should be considered as an initial 

treatment approach for these women. (NICHD) 

References: 

Brubaker L, et al. Abdominal sacrocolpopexy with burch colposuspension to reduce urinary 

stress incontinence. N Engl J Med. 2006 Apr 13;354(15):1557-66. 

Rogers RG. What’s best in the treatment of stress urinary incontinence? N Engl J Med. 2010 

Jun 3;362(22):2124-5. 

Subak LL, Whitcomb E, Shen H, Saxton J, Vittinghoff E, Brown JS. Weight loss: a novel and 

effective treatment for urinary incontinence. J Urol. 2005 Jul;174(1):190-5. 

35
A Novel Program Enhances Quality of Life for Caregivers of 

Alzheimer’s Patients 

Family caregivers of people with Alzheimer’s disease (AD) are disproportionately female. 

NIA-supported investigators have demonstrated that a personalized intervention consisting 

of home visits, structured telephone support sessions, and telephone “check-ins” can 

significantly improve the quality of life for AD caregivers. Subsequent research has shown 

that caregivers who receive this intervention report better self-rated health, sleep quality, 

physical health, and emotional health than caregivers not receiving the intervention. The 

study, Resources for Enhancing Alzheimer’s Caregiver Health II (REACH II), was funded 

by NIA and the NINR and is the first randomized controlled trial to look at the effectiveness 

of an AD caregiver support intervention for ethnically diverse populations. The first national 

clinical translation of REACH II, REACH VA, has been implemented by the Veterans Health 

Administration Geriatrics and Extended Care Unit in partnership with the Memphis VA 

Medical Center. NIA is also working with the AoA to translate the REACH intervention 

at the community level. (NIA) 

References: 

Belle SH, et al. Enhancing the quality of life of dementia caregivers from different ethnic or 

racial groups: a randomized, controlled trial. Ann Intern Med. 2006;145(10):727-38. 

Elliott AF, Burgio LD, Decoster J. Enhancing caregiver health: findings from the resources for 

Enhancing Alzheimer’s Caregiver Health II intervention. J Am Geriatr Soc. 2010;58(1):30-7. 

Ginkgo Biloba Does Not Reduce Risk of Alzheimer’s Disease 

Important scientific insights have been obtained from a major, long-term clinical trial, the 

Ginkgo Evaluation of Memory Study (GEMS). This study found that the dietary supplement 

Ginkgo biloba was ineffective in reducing the development of dementia and Alzheimer’s disease in older people. In addition to funding from NCCAM, the GEMS received support from 

four other NIH components: NIA, NHLBI, NINDS, and ODS. (NCCAM) 

Reference: 

DeKosky ST, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. 

JAMA. 2008;300(19):2253-62. Erratum in: JAMA. 2008 Dec 17;300(23):2730. 

36
Vitamin D and Calcium Supplementation Reduce Fall Risk in Older Women 

According to data from the CDC, more than one-third of U.S. adults ages 65 and older fall 

each year. Among older adults, falls are the leading cause of deaths due to injury and are 

also the most common cause of nonfatal injuries and hospital admissions for trauma. In 

a groundbreaking 2006 study, dietary supplementation with vitamin D and calcium was 

shown to reduce risk of falling by 46 percent in ambulatory older women overall and by 65 

percent in women who were ambulatory but less physically active. No significant effects of 

this regimen were observed in men. Because supplementation with calcium and vitamin D 

is one of the least burdensome and expensive treatment strategies and is associated with 

relatively few side effects, efforts to reduce falls and improve skeletal health in older 

women have increasingly incorporated an emphasis on 

calcium and vitamin D supplementation. (NIA) 

Reference: 

Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B. Effect of cholecalciferol plus calcium on 

falling in ambulatory older men and women: a 3-year randomized controlled trial. Arch 

Intern Med. 2006;166(4):424-30. 

Determination of RDA for Vitamin D in Caucasian and 

African-American Women 

The prevalence of osteoporosis is high in United States, with about 10 million people over the 

age of 50 already having the disease and another 34 million at risk for developing osteoporosis. However, optimal daily intake for postmenopausal women has not been scientifically 

established. NIH-supported investigators are conducting studies to establish the RDA for 

vitamin D in older women, which will have important implications for efforts to prevent 

osteoporosis in this population. (ODS) 

37
Examples of Cancer in Women 

CERvICAL CANCER 

The HPV Cervical Cancer Vaccine and HPV-based Cervical Cancer Screening 

Cervical cancer is the second most common cause of death from cancer among women worldwide. Since 1990, epidemiologic studies have validated the fact that human papillomavirus 

(HPV) infection is the main cause of virtually all cases of cervical cancer. These results have 

led to the development of a highly effective vaccine to prevent cervical cancer and other 

HPV-associated diseases, and to HPV-based cervical cancer screening procedures. NCI has 

been involved in all of these etiology-based advances, and vaccine development was strongly 

supported by the ORWH. The vaccine can reduce the incidence of cervical cancer by about 

70 percent, and second generation vaccines under development have the potential to reduce 

it even further. HPV-based testing can improve current cervical cancer screening programs 

in the United States and other industrialized nations. Its relatively low cost also makes HPV 

testing a feasible and effective screening test for use in developing nations, where increasing 

screening rates has the potential to reduce the incidence of cervical cancer sooner than by 

immunizing with the vaccine. (NCI) 

References: 

Muñoz N, Kjaer SK, Sigurdsson K, et al. Impact of the human papillomavirus (HPV)-

6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 

2010;102(5):325-39. 

Paavonen J, Naud P, Salmerón J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-

adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types 

(PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 

2009;374(9686):301-14. 

Plummer M, et al. A 2-year prospective study of human papillomavirus persistence among 

women with a cytological diagnosis of atypical squamous cells of undetermined significance 

or low-grade squamous intraepithelial lesion. J Infect Dis. 2007;195(11):1582-9. 

BREAST CANCER 

Genes and Other Risk Factors 

BRCA1 and BRCA2 Identification in Familial Breast and Ovarian Cancer 

Inactivating mutations of the BRCA1 and BRCA2 genes have been linked to an elevated risk 

of developing breast and ovarian cancer. They are the first genes identified as causing familial breast cancer. Their discovery has enabled better-informed genetic counseling for members 

of families that carry mutant alleles, contributed to the management of these patients, and 

brought insight to the normal function of these genes and how their inactivation in patients 

38
can contribute to the development of cancer. Surgery that removes the ovaries and fallopian 

tubes, called salpingo-oophorectomy, has been demonstrated to decrease a woman’s risk of 

breast and ovarian cancer if she carries a BRCA1 or BRCA2 gene mutation. The research studies that led to these advances were strongly supported by NCI. (NCI)
�

References:
�

Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 

1999;91(15):1310-6.
�

Kadouri L, Hubert A, Rotenberg Y, Hamburger T, Sagi M, Nechushtan C, Abeliovich D, Peretz T. Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. J Med Genet.
�

2007;44(7):467-71.
�

Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated 

with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer 

Inst. 2009;101(2):80-7.
�

Thompson D, Easton DF, et al. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 

2002;94(18):1358-65.
�

Discovery of the BRCA1 Gene 

For millions of women whose lives have been affected by breast cancer, the 1994 discovery 

of the first breast cancer gene by researchers from NIEHS was a welcome sign of progress in 

the fight against this dreaded disease. Diagnostic tests can now identify women who have 

inherited defective copies of the gene and are more likely to develop breast cancer. (NIEHS) 

Reference: 

Futreal PA, Cochran C, Marks JR, Iglehart JD, Zimmerman W, Barrett JC, Wiseman RW. 

Mutation analysis of the THRA1 gene in breast cancer: deletion/fusion of the gene to a 

novel sequence on 17q in the BT474 cell line. Cancer Res. 1994 Apr 1;54(7):1791-4. 

Studies of BRCA1 and Other Breast Cancer Genes 

An intramural NHGRI laboratory investigates mutations in two known breast-cancer-linked 

genes, breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2), and their roles in 

inherited breast and ovarian cancer susceptibility. In 1994, this laboratory was among the first 

to report that women carrying BRCA1 or BRCA2 mutations have a higher risk of developing 

both breast and ovarian cancer than women without such mutations. The group also discovered an unusually high frequency of specific BRCA1 mutations in the Jewish population. They 

recently helped identify eight distinct protein-shortening mutations and another six rare 

variations of BRCA2 in a group of African-American breast and ovarian cancer patients. 

The team is continuing to study these two populations to better understand the risk of cancer 

associated with specific mutations and is collecting information on all identified mutations in 

these two genes worldwide. Currently, more than 2,000 distinct BRCA1 and BRCA2 mutations 

have been identified. Because women with BRCA1 mutations account for only 5 percent of all 

39
breast cancer cases diagnosed every year, there is a growing scientific consensus that not all 

BRCA mutations carry the same risk of cancer. 

The group also is investigating how normal BRCA genes help maintain healthy cells. They previously demonstrated that the normal BRCA1 protein regulates key effectors that control the 

G2/M DNA damage checkpoint, a cell-cycle checkpoint that prevents cells with genomic damage from entering mitosis and reproducing. The carboxyl terminus of BRCA1 contains two 

motifs found in several DNA-repair and cell-cycle checkpoint proteins. The laboratory also 

demonstrated that these motifs also bind to a number of other nuclear proteins critical to DNA 

replication. This segment of BRCA1 also interacts with several histone deacetylases, proteins 

that modulate the transcriptional activity of genes leading to cell growth arrest, cellular differentiation, and apoptosis (programmed cell death). 

Research has found that the amino terminus of BRCA1 is a RING finger protein, a class of proteins that have ligase activity. This ligase catalyzes a key enzymatic step in the ubiquitination 

pathway, a cellular pathway that recognizes misfolded proteins and targets them for degradation, thus keeping the cell functioning normally. Defects in the normal ubiquitination pathway 

are implicated in a range of illnesses, including cancer. This particular team is working to identify all the molecules in the ubiquitination pathway that interact with BRCA1. 

In addition, NHGRI funds numerous extramural projects related to breast cancer. These include 

development of an interactive CD-ROM on cancer genetics for Hispanic populations, analysis of parent communication of BRCA1/2 testing results to children, economic evaluations of 

emerging genomics tests for early-stage breast cancer, and the development of many highthroughput cancer genome sequencing and mapping centers. (NHGRI) 

Genes Associated With Aggressive Breast Cancer in African Women 

Although incidence rates of breast cancer are lower in African-Americans than in Caucasians 

overall, African-American women have a higher incidence under 40 years of age, are diagnosed with more advanced disease, and have poorer prognoses. Groundbreaking NIH research 

in West Africa revealed evidence of a genetic predisposition to more aggressive forms of 

breast cancer. In Nigeria, researchers identified three genes that may contribute to high fatality 

rates and insensitivity to treatment of breast cancer in African women compared with Caucasian women. These findings underscore the urgent need for research into the etiology and 

treatment of the aggressive molecular subtypes that disproportionately affect young 

African women in the United States and globally. This study was funded by NCI. (NCI, FIC) 

Reference: 

Huo D, Ikpatt F, Khramtsov A, Dangou JM, Nanda R, Dignam J, Zhang B, Grushko T, Zhang C, 

Oluwasola O, Malaka D, Malami S, Odetunde A, Adeoye AO, Iyare F, Falusi A, Perou CM, Olopade OI. Population differences in breast cancer: survey in indigenous African women reveals 

over-representation of triple-negative breast cancer. J Clin Oncol. 2009 Sep 20;27(27):4515-21. 

40
Large Surveys Explored Various Risk Factors for Breast Cancer 

Approximately 200,000 women are diagnosed with breast cancer each year. Of women 

born in the United States since 1945, approximately 80 percent have used oral contraceptives. Previous research suggested a slightly elevated risk of breast cancer among women 

who had recently taken oral contraceptives. The NICHD Women’s Contraceptive and Reproductive Experiences Study (Women’s CARE) included interviews with more than 9,000 

white and black women between the ages of 35 and 64 in various cities across the United 

States. Women in this study were asked about their use of oral contraceptives and other hormones as well as their reproductive, family, and health histories. The researchers concluded 

that there was no association between use of oral contraceptives and breast cancer among 

women between the ages of 35 and 64. 

Information collected as part of NICHD’s Women’s CARE Study was also used by researchers at NICHD, NHGRI, and other institutions to estimate the prevalence in the United States 

of two genetic mutations that confer a greatly increased risk of breast cancer. The data suggested that the prevalence of BRCA1 mutations among women ages 35-64 is approximately 

0.06 percent, and the prevalence of BRCA2 mutations is 0.4 percent. These inherited mutations, known as Breast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2), may be involved in 

between 5 and 27 percent of all breast cancer cases. The researchers also identified factors 

that increase the likelihood that a woman carries a BRCA1 or BRCA2 mutation, such as early 

age of onset of breast cancer in the patient or family members. The study was also notable 

because it included understudied groups, such as African-Americans and older women, in its 

analysis. (NICHD) 

References: 

Malone KE, Daling JR, Doody DR, Hsu L, Bernstein L, Coates RJ, Marchbanks PA, Simon 

MS, McDonald JA, Norman SA, Strom BL, Burkman RT, Ursin G, Deapen D, Weiss LK, Folger 

S, Madeoy JJ, Friedrichsen DM, Suter NM, Humphrey MC, Spirtas R, Ostrander EA. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast 

cancer in white and black American women ages 35 to 64 years. Cancer Res. 2006 Aug 

15;66(16):8297-308. 

Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, 

Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, 

Spirtas R, Weiss LK. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002 

Jun 27;346(26):2025-32. 

Breast Density in Mammography and Cancer Risk 

Multiple studies have established that breast density is directly linked to breast cancer risk. 

Women with the highest densities are estimated to have a threefold or greater risk compared 

with women with the lowest densities. Though this risk can be influenced by lifestyle factors, 

twin studies show that the underlying causes of breast density are mostly inherited. Higher 

breast density is more common in some ethnic groups, including white women. It is also more 

common in younger women, beginning with increased hormone production during puberty 

41
and continuing through the childbearing years. To identify women at higher risk for breast 

cancer, NCI’s Breast Cancer Surveillance Consortium developed and published risk prediction 

models. (NCI) 

References: 

Boyd NF, Martin LJ, Bronskill M, Yaffe MJ, Duric N, Minkin S. Breast tissue composition and 

susceptibility to breast cancer. J Natl Cancer Inst. 2010 Aug 18;102(16):1224-37. 

Kerlikowske K, Ichikawa L, et al. Longitudinal measurement of clinical mammographic breast 

density to improve estimation of breast cancer risk. J Natl Cancer Inst. 2007;99(5):386-95. 

Tice JA, Cummings SR, Smith-Bindman R, Ichikawa L, Barlow WE, Kerlikowske K. Using clinical 

factors and mammographic breast density to estimate breast cancer risk: development 

and validation of a new predictive model. J Natl Cancer Inst. 2007;99(5):386-95. 

Tice JA, Cummings SR, Ziv E, Kerlikowske K. Mammographic breast density and the Gail 

model for breast cancer risk prediction in a screening population. Breast Cancer Res Treat. 

2005;94(2):115-22. 

The NIEHS/NCI Breast Cancer and the Environment Research Program 

The NIEHS/NCI Breast Cancer and the Environment Research Program is one of the first 

attempts designed to determine how local environmental factors and genetics predispose 

young women to breast cancer later in life and to share the findings with the breast cancer 

community and the public at large. Among its accomplishments to date are pilot biomarker 

studies on blood and urine from girls—conducted in collaboration with CDC—that indicate 

the presence of a wide spectrum of hormonally active exposure biomarkers. Several of these 

chemicals had not been previously reported for school-age girls and may have important 

effects on their development through puberty. 

A recent study by the program shows some association of common environmental exposures, such as phthalates, with changes in early childhood development. The thought is that 

these exposures may accelerate the beginning of puberty in girls, an event that is a risk factor 

for breast cancer in adult women. These seemingly small advances can prove to be significant 

in allowing girls and their families to take steps to change their risk profile for breast cancer. 

(NIEHS and NCI) 

References: 

Wolff MS, Teitelbaum SL, Windham G, Pinney SM, Britton JA, Chelimo C, Godbold J, Biro F, 

Kushi LH, Pfeiffer CM, Calafat AM. Pilot study of urinary biomarkers of phytoestrogens, phthalates, and phenols in girls. Environ Health Perspect. 2007;115(1):116-21. 

Wolff MS, Teitelbaum SL, et al. Investigation of relationships between urinary biomarkers of 

phytoestrogens, phthalates, and phenols and pubertal stages in girls. Environ Health Perspect. 

2010 Jul;118(7):1039-46. 

42
The Sister Study Examines Environmental and Genetic Risk Factors for Breast 

Cancer in a Diverse Population of Women 

The Sister Study, a unique public-private partnership, seeks to identify some of the genetic 

and environmental causes of breast cancer. The Sister Study is cofunded by NCMHD and led 

by NIEHS. The Sister Study is the only long-term study in the United States and Puerto Rico 

of women ages 35 to 74 whose sisters have had breast cancer. Begun in 2003, the study prospectively examines the environmental and familial risk factors for breast cancer and other 

diseases in a cohort of 50,000 sisters of women who have had breast cancer. Initial research 

of the Sister Study has found that women who maintain a healthy weight and who have lower 

perceived stress seem to slow the aging process and live healthier lives. NCMHD support has 

assisted in the recruitment and retention of a diverse cohort of women, including AfricanAmericans, Asians, American Indians/Alaska Natives, Hispanics, and seniors (age 65 and 

older). (NIEHS and NCMHD) 

References: 

Kim S, Parks CG, DeRoo LA, Chen, H, Taylor JA, Cawthon RM, Sandler DP. Obesity and weight gain 

in adulthood and telomere length. Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):816-20. 

Parks CG, Miller DB, McCanlies EC, Cawthon RM, Andrew ME, DeRoo LA, Sandler, DP. Telomere 

length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiol 

Biomarkers Prev. 2009 Feb;18(2):551-60. 

http://www.niehs.nih.gov/news/releases/2009/sister-study.cfm 

Breast Cancer Prevention 

Breast Cancer Prevention Trial Study of Tamoxifen and Raloxifene 

The Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR) 

demonstrated that half of breast cancers can be prevented with a medical intervention and provided a beginning from which a new paradigm for breast cancer prevention is evolving. Women 

at increased risk of this common disease now have preventive options where none had existed. 

Cohorts of women at increased risk for breast cancer who could derive a net benefit from 

receiving tamoxifen or raloxifene have been identified and are being studied. Neither tamoxifen 

nor raloxifene is without risk of side effects, but these studies have shown that premenopausal 

women are likely to derive benefit from tamoxifen with few serious side effects, and postmenopausal women have fewer risks with the drug raloxifene. Analyses of blood, tissue, and clinical 

data from these studies continue to answer vital questions about breast cancer biology, risk, 

and prevention, and about who is most likely to benefit from these drugs. (NCI) 

References: 

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for 

prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project 

P-1 study. J Natl Cancer Inst. 1998;90(18):1371-88. 

43
Vogel VG, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of 

Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila 

PA). 2010 Jun;3(6):696-70. 

Vogel VG, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast 

cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 

trial. JAMA. 2006 Jun 21;295(23):2727-4. 

Physical Activity Reduces Breast Cancer Risk and Improves Survival 

Research shows that women who exercise are less likely to develop breast cancer than their 

sedentary peers; physical activity can also improve outcomes for those patients who do 

develop breast cancer. One of the largest surveys administered found an 18 percent drop in 

the risk of the disease for women who walked briskly for 75 to 150 minutes each week compared with women who were less active. While researchers continue to study how exercise 

reduces cancer risk, they hypothesize that it may be related to the amount of body fat; fat 

cells tend to release more estrogen, which is known to promote some types of breast cancer. 

Other studies have provided evidence that physical activity improves survival and reduces 

negative treatment side effects. (NCI) 

References: 

Alfano CM, Smith AW, Irwin ML, Bowen DJ, Sorensen B, Reeve BB, Meeske KA, Bernstein L, 

Baumgartner KB, Ballard-Barbash R, Malone KE, McTiernan A. Physical activity, long-term 

symptoms, and physical health-related quality of life among breast cancer survivors: a prospective analysis. J Cancer Surviv. 2007;1(2):116-28. 

Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical activity and survival 

after breast cancer diagnosis. JAMA. 2005;293(20):2479-86. 

Irwin ML, Smith AW, McTiernan A, Ballard-Barbash R, Cronin K, Gilliland FD, Baumgartner RN, 

Baumgartner KB, Bernstein L. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the Health, Eating, Activity, and Lifestyle study. J Clin Oncol. 

2008;26(24):3958-64. 

Maruti SS, Willett WC, Feskanich D, Rosner B, Colditz GA. A prospective study of age-specific 

physical activity and premenopausal breast cancer. J Natl Cancer Inst. 2008;100(10):728-37. 

Artificial Light at Night Stimulates Breast Cancer Growth 

Results from a study in laboratory mice show that nighttime exposure to artificial light 

stimulates the growth of human breast tumors by suppressing the levels of a key hormone 

called melatonin. The study also showed that extended periods of nighttime darkness 

greatly slowed the growth of these tumors. The study results might explain why female 

night shift workers have a higher rate of breast cancer. It also offers a promising new 

explanation for the epidemic rise in breast cancer incidence in industrialized countries 

like the United States. (NIEHS) 

44
References: 

Blask DE, Brainard GC, Dauchy RT, Hanifin JP, Davidson LK, Krause JA, Sauer LA, Rivera-Bermudez MA, Dubocovich ML, Jasser SA, Lynch DT, Rollag MD, Zalatan F. Melatonin-depleted 

blood from premenopausal women exposed to light at night stimulates growth of human 

breast cancer xenografts in nude rats. Cancer Res. 2005 Dec 1;65(23):11174-84. 

http://www.niehs.nih.gov/news/releases/news-archive/2005/cancerlight.cfm 

Timing of Dietary Exposure and Breast Cancer Risk 

Epidemiological studies have not consistently linked any specific dietary component to 

either increased or reduced breast cancer risk. However, some researchers believe that timing of dietary exposures might be more important in affecting risk than an exposure shortly 

before or at diagnosis, and that the breast is most sensitive to dietary factors at times when 

diet-induced biological changes can alter its development and function. These sensitive 

periods include fetal life, puberty, and pregnancy, when the breast undergoes extensive 

proliferation following a natural exposure to high levels of hormones and growth factors, 

which are known to play a central role in breast cancer. NIH-supported investigators are 

currently studying the timing of exposures to various nutritional components that interact 

with nuclear hormone receptors, with the ultimate aim of developing novel means to prevent some breast cancers by dietary modifications that take place during pregnancy and 

puberty. (ODS) 

Declines in Breast Cancer Incidence Linked to Reduced Use of Menopausal 

Hormone Therapy 

After rising for more than two decades, the incidence of breast cancer in the United States 

decreased sharply in 2003 and has remained at the lower level. Researchers attribute the 

drop to a decrease in the use of menopausal hormone therapy (MHT) that occurred at about 

the same time. Starting in mid-2002, millions of women stopped using MHT after an NIH 

study linked certain hormones to health risks, including breast cancer. These studies relied 

heavily on data from the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program. 

The declines were more significant in breast cancers that were estrogen receptor positive, the 

specific type of cancer whose growth can be fueled by the use of MHT. (NCI) 

References: 

Ross RK, Paganini-Hill A, Wan PC, Pike MC. The decrease in breast-cancer incidence in 2003 in 

the United States. N Engl J Med. 2007;356(16):1670-4. 

Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast 

cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92(4):328-32. 

45
Screening, Detection, and Diagnosis of Breast Cancer 

Early Breast Cancer Detection—Breast CT Scanner 

Breast cancer is the second most common cancer found among American women, with 

approximately 200,000 new cases reported each year. One method of early detection of 

breast cancer is getting women screened for breast cancer regularly. Mammograms, or 

x-rays of the breast, are used to detect breast cancer in women with no signs or symptoms 

of the disease in order to find and treat small lesions before cancer spreads. However, the 

pinch that occurs when breasts are squeezed between two plates during a mammogram 

is enough to make some women avoid this potentially life-saving screening procedure. 

A new approach to breast imaging—a dedicated breast scanner based on computed 

tomography (CT)—may someday offer women pain-free screening as well as more precise 

diagnosis and treatment options. Using x-rays taken from many different angles, breast 

CT provides a three-dimensional image of the breast using the same amount of radiation 

as that used for a mammogram. The scanner system, developed by researchers at the 

University of California, Davis, images and exposes only the breast to radiation, using cone 

beam geometry. This scanner protects the surrounding tissue in the lungs, heart, and back 

from radiation exposure. As a potential screening tool, the breast CT scanner surpasses 

conventional mammography in several ways: it provides three-dimensional images of 

the breast compared with just two-dimensional images for mammography, eliminates 

compression of the breast between two plates, and eliminates image artifacts (suspicious 

areas that result from normal breast structures overlaying each other when the breast 

compresses). Women with dense breasts may particularly benefit from this more detailed 

imaging, since dense breast tissue can obstruct lesions. (NIBIB) 

Reference: 

Lindfors KK, Boone JM, Nelson TR, Yang K, Kwan AL, Miller DF. Dedicated breast CT: initial 

clinical experience. Radiology. 2008 Mar;246(3):725-33. 

Self-hypnosis Reduces Anxiety and Pain during Core Needle Breast Biopsy 

An NCCAM-funded trial found that women who used self-hypnosis during a type of core 

needle breast biopsy experienced anxiety relief and reduced pain when compared with 

standard care. Specifically, the study found that both self-hypnosis and empathic attention 

reduced pain and anxiety during the procedure with self-hypnosis providing greater anxiety relief. Neither intervention increased procedure time or significantly increased cost. As 

a result, the researchers suggest that self-hypnosis appears attractive for outpatient pain 

management. (NCCAM) 

Reference: 

Lang EV, Berbaum KS, Faintuch S, Hatsiopoulou O, Halsey N, Li X, Berbaum ML, Laser E, 

Baum J. Adjunctive self-hypnotic relaxation for outpatient medical procedures: a prospective randomized trial with women undergoing large core breast biopsy. Pain. 2006 Dec 

15;126(1-3):155-64. 

46
Magnetic Resonance Spectroscopy Imaging (MRSI) for Characterizing 

Breast Cancers 

MRI is increasingly being used as an imaging tool for management of breast cancer, for 

such purposes as local staging and screening for high-risk patients. Researchers at the NCRRsupported Biomedical Research Center at the University of Minnesota have explored the use 

of Magnetic Resonance Spectroscopy Imaging (MRSI) for characterizing breast cancers and 

demonstrated its efficacy in improving diagnostic accuracy and monitoring response to therapy. Specifically, they have shown that the concentration of choline-containing compounds, 

measured by MRSI, can serve as sensitive biomarkers for breast malignancies. (NCRR) 

Classifying Breast Cancers by Gene Expression Profiling 

In the last decade, the development of microarrays and the ability to carry out gene expression profiling have resulted in a new way of classifying breast cancers and have established 

the heterogeneity among breast cancers at the molecular level. Gene profiling has led to identification of four subtypes of breast cancers: luminal A (ER+/PR+/Her2-), luminal B (ER+/PR+/ 

Her2+), Her2+ (ER-/Her2+) and basal (ER-/PR-/Her2-). The information from gene profiling is 

now being used to determine treatment decisions. (NCI) 

References: 

Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, Kerkhoven RM, 

van Vliet MH, Wessels LF, Peterse JL, Berns A, Jonkers J. Somatic loss of BRCA1 and p53 in 

mice induces mammary tumors with features of human BRCA1-mutated basal-like breast 

cancers. Proc Natl Acad Sci USA. 2007;104(29):12111-6.
�

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen 

H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, BørresenDale AL, Brown PO, Botstein D. Molecular portraits of human breast tumors. Nature. 2000; 

406(6797):747-52.
�

Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, Savage K, Gillett CE, 

Schmitt FC, Ashworth A, Tutt AN. BRCA1 dysfunction in sporadic basal-like breast cancer. 

Oncogene. 2007;26(14):2126-32.
�

Weigelt B, Baehner FL, Reis-Filho JS. The contribution of gene expression profiling to breast 

cancer classification, prognostication and prediction: a retrospective of the last decade. J 

Pathol. 2010 Jan;220(2):263-80.
�

NIH Consensus Development Conference: Breast Cancer Screening for 

Women Ages 40-49, January 21-23, 1997 

NCI and OMAR convened an independent panel in 1997 to assess the available scientific data 

on the effectiveness of mammography screening for women ages 40-49. Panel members 

took into consideration the risks versus the benefits of mammography screening and found 

that the available evidence for a breast cancer mortality reduction for women in their forties 

was inconsistent, while the risks of false-positive and false-negative mammograms and radiation-induced breast cancers appeared greater in this age group. As such, they did not think 

that the data supported a recommendation for universal mammography screening for all 

47
women in their forties and concluded that each woman should be able to individually decide 

whether to undergo mammography.1 They noted the decision should be based upon access 

to the best possible information regarding benefits and risks, presented in an understandable and usable form. The panel believed that the costs of mammograms for all women in 

their forties choosing to undergo mammography should be reimbursed by third-party payors or covered by health maintenance organizations. The panel identified a number of critical 

research questions, including the optimal screening interval for women of various ages, the 

relationship between the magnitude of breast-cancer mortality reduction and the age of 

the woman beginning mammography, and the impact of menopause on the effectiveness of 

mammography. (OMAR) 

Advances in Treatment of Breast Cancer 

Treatment for HER-2-Positive Invasive Breast Cancer 

Results from two large, randomized clinical trials conducted by the NCI-sponsored Clinical 

Trials Cooperative Group Program for patients with HER-2-positive invasive breast cancer 

demonstrated that women with early-stage breast cancer who received Herceptin® (trastuzumab, a monoclonal antibody to the HER-2 protein) in combination with chemotherapy 

reduced their risk of recurrence by 52 percent after three years compared with women who 

received the same chemotherapy regimen without trastuzumab. For women with this type of 

aggressive breast cancer, the addition of trastuzumab to chemotherapy appears to virtually 

reverse prognosis from unfavorable to good. These findings represent a triumph for molecularly targeted cancer treatment and a noteworthy advance in breast cancer treatment that has 

changed the standard of care for the 25 to 30 percent of women whose tumors express the 

HER-2 protein. (NCI) 

Reference: 

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, 

Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher 

DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, 

Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-84. 

Aromatase Inhibitors 

Since the mid-1990s there has been a series of clinical trials of third-generation aromatase 

inhibitors demonstrating their effectiveness in treating breast cancer. Both anastrozole and 

letrozole have been approved as first-line endocrine therapy for postmenopausal estrogenreceptor-positive advanced breast cancer patients. Several studies have shown that about 60 

percent of breast tumors have significant levels of aromatase and thus are able to carry out 

local synthesis of estrogens. An intratumoral aromatase model in nude mice which simulates 

1 The NIH Consensus Statement on Breast Cancer Screening for Women Ages 40-49 contains a minority 

report. While a consensus was initially achieved by the entire panel at the end of the conference, 2 of the 12 

panel members subsequently decided that the risks of mammography were overemphasized by the majority 

and concluded the data did support a recommendation for mammography screening for all women in this 

age group. 

48
the postmenopausal breast cancer patient was found to be extremely useful in determining 

the efficacy of aromatase inhibitors and accurately predicting clinical response. This model 

was used in investigating the efficacy of combining tamoxifen with an aromatase inhibitor and 

demonstrated that the aromatase inhibitor alone was more effective than either tamoxifen 

alone or tamoxifen combined with the aromatase inhibitor. This was found to be true in clinical 

trials as well. (NCI) 

References: 

Baum M, et al. Anastrazole alone or in combination with tamoxifen versus tamoxifen alone for 

adjuvant treatment of postmenopausal women with early stage breast cancer: results of the 

ATAC trial efficacy and safety update analyses. Cancer. 2003;98(9):1802-10. 

Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Goloubeva OG, 

Brodie AM. Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a 

breast cancer model. J Natl Cancer Inst. 2004;96(6):456-65. 

Understanding Racial Disparities in Underuse of Treatment for Early-Stage 

Breast Cancer 

Reducing Underuse of Early-stage Breast Cancer Treatment in Minority Communities is a project measuring the extent of underuse of efficacious breast cancer treatments among patients 

of six hospitals serving East and Central Harlem and other minority communities in lower Manhattan with the intent of solving problems of underuse of effective interventions in patients 

with early-stage breast cancer. This study has generated new knowledge about racial disparities in treatment for early-stage breast cancer and patient and physician reasons for underuse, 

and is exploring the effectiveness of a simple, sustainable intervention to improve rates of 

efficacious cancer treatment. To date, they have completed chart abstraction of over 1,000 

identified breast cancer cases from six different hospitals. In a study of the records of nearly 

700 women, they found an overall disparity in underuse of 19 percent, with the following 

breakdown: 14 percent underuse for whites, 23 percent for Hispanics, and 30 percent for 

African-Americans. They are currently looking for the factors that may explain this underuse 

data and have completed a small number of patient and surgeon surveys. A computer-based 

intervention is currently ongoing at three of the six participating hospitals. (NCMHD) 

Hypnosis May Reduce Hot Flashes in Breast Cancer Survivors 

NCCAM-supported researchers investigated the effects of hypnosis on hot flashes in a study of 

60 women with a history of primary breast cancer, no current evidence of detectable disease, 

and at least 14 hot flashes per week over a one-month period. They concluded that hypnosis 

not only appears to reduce perceived hot flashes in breast cancer survivors, but may also have 

additional benefits such as improved mood and sleep. They are now conducting a randomized 

clinical trial with 200 participants. (NCCAM) 

Reference: 

Elkins G, Marcus J, Stearns V, Perfect M, Rajab MH, Ruud C, Palamara L, Keith T. Randomized 

trial of a hypnosis intervention for treatment of hot flashes among breast cancer survivors. J 

Clin Oncol. 2008 Nov 1;26(31):5022-6. 

49
Antidepressants for Hot Flashes May Interfere with Tamoxifen 

Women with breast cancer often take the drug tamoxifen to treat the cancer and antidepressants to ease the depression and hot flashes that are side effects of the cancer drug. However, 

a study led by a clinical pharmacologist at the Indiana University School of Medicine in Indianapolis and a member of the NIH Pharmacogenetics Research Network, shows that a common 

class of antidepressants, called selective serotonin reuptake inhibitors, can hinder the effectiveness of tamoxifen. The findings also point to genetic differences that may explain why 

tamoxifen works well in some women and not others, and why some people respond better to 

certain antidepressants. The new information could help doctors make more informed choices 

about what drugs are likely to work best for different patients. (NIGMS) 

Reference: 

Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, 

Flockhart DA. Active tamoxifen metabolite plasma concentrations after coadministration 

of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 

2003 Dec 3;95(23):1758-64. 

Genes Influence Response to Breast Cancer Treatment 

A major focus in pharmacogenetics research is on a large group of enzymes that process 

many medications in the body. Researchers supported by the Pharmacogenetics Research 

Network studying women with breast cancer found that individuals with a specific genetic 

variation in one such enzyme (CYP2D6) do not respond as well as those without the variation 

to tamoxifen, a widely prescribed drug used to treat breast cancer. On average, breast cancer survivors with the CYP2D6 variation live disease free for only four years after treatment, 

whereas those without the variation average eleven years disease free. This discovery may 

lead to greater use of genetic tests to determine which women are most likely to benefit 

from tamoxifen. (NIGMS) 

References: 

Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard 

R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart 

DA. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast 

cancer treatment. J Natl Cancer Inst. 2005 Jan 5;97(1):30-9. 

Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, 

Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 

2005 Dec 20;23(36):9312-8. 

Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, Jin Y, Storniolo AM, Nikoloff DM, Wu 

L, Hillman G, Hayes DF, Stearns V, Flockhart DA. Quantitative effect of CYP2D6 genotype and 

inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. 

Clin Pharmacol Ther. 2006;80(1):61-74. 

50
NIH State-of-the-Science Conference: Diagnosis and Management of Ductal 

Carcinoma in Situ, September 22–24, 2009 

NCI and OMAR cosponsored the NIH State-of-the-Science Conference: Diagnosis and Management of Ductal Carcinoma in Situ in September 2009. Ductal carcinoma in situ of the breast, or 

DCIS, represents a spectrum of abnormal cells confined to the breast duct and is a risk factor 

for invasive breast cancer development. The independent State-of-the-Science Panel convened to weigh the available evidence associated with DCIS in 2009 found that because of the 

noninvasive nature of DCIS and its favorable prognosis, strong consideration should be given 

to removing the anxiety-producing term “carcinoma” from the description of DCIS. The outcomes in women treated with available therapies are excellent. Thus, the primary question for 

future research must focus on the accurate identification of patient subsets diagnosed with 

DCIS, including those persons who may be managed with less-invasive intervention, without 

sacrificing the excellent outcomes presently achieved. (OMAR) 

OvARIAN CANCER 

Genetic Research on Ovarian Cancer 

About one-fifth of ovarian cancers are found at an early stage. Early detection improves the 

chances that it can be treated successfully. Nine out of 10 women treated for early ovarian 

cancer will live longer than five years after the cancer is found. Unfortunately, there is no reliable test for finding this cancer early, but several large studies are in progress to learn how 

best to find ovarian cancer in its earliest stages. 

Currently, NHGRI researchers are in the pilot phase of a collaborative project to identify locations in the genome that are important for the regulation of gene expression in ovarian 

cancers. By using sequencing to identify sites of abnormal methylation (a DNA modification) in promoter regions, this project hopes to determine which regulatory regions and which 

genes are factors in the occurrence of ovarian cancer. Investigators at NHGRI were among the 

first to report that women carrying BRCA1 or BRCA2 mutations have a higher risk for Hereditary Breast Ovarian Cancer (HBOC) Syndrome. NHGRI noticed a lack of studies regarding 

knowledge, attitudes, and behaviors related to cancer genetics among Hispanic women at 

increased risk for HBOC among various Hispanic ethnic groups. 

NHGRI has awarded a grant to better understand cultural differences that may affect utilization of BRCA1/2 testing for HBOC among three major U.S. Hispanic ethnic groups (Mexicans, 

Puerto Ricans, and Cubans). Study findings will serve as the basis for a larger intervention 

trial based in a public health department setting to educate Hispanic women at increased 

risk for HBOC about genetic counseling and testing for HBOC and possibly other hereditary 

cancers. (NHGRI) 

51
Mifepristone Reduces Ovarian Cancer Cell Growth between Rounds 

of Chemotherapy 

The majority of ovarian cancer patients require surgery to remove as much of the tumor as 

possible, followed by chemotherapy that includes a platinum compound such as cisplatin 

or carboplatin. However, platinum-based chemotherapy is hindered by the elevated toxicity of the drug, the development of chemoresistance, and the capacity to regenerate tumors 

of surviving tumor cells (repopulation) between rounds of chemotherapy. One strategy to 

stop tumor cell repopulation is to use a selective compound between courses of chemotherapy to inhibit repopulation of tumor cells. Researchers at the NCRR-supported Sanford 

School of Medicine of The University of South Dakota are investigating the use of mifepristone (commonly known as “RU-486”) to reduce either the number of cisplatin cycles or the 

dose of cisplatin without losing efficacy in inhibiting tumor growth. Consequently, scheduling mifepristone treatment between courses of platinum-based therapy for ovarian cancer 

has potential to improve treatment success. (NCRR) 

UTERINE/ENDOMETRIAL CANCER 

Genetics of Endometrial Cancer 

Endometrial cancer, which affects the endometrium (the lining of the uterus), is the most 

common gynecological malignancy in the United States. There are 41,200 new cases of endometrial cancer diagnosed each year, along with 7,350 deaths attributable to this disease. Most 

patients present with “type I” tumors and have a good prognosis, but around 15 percent are 

diagnosed with “type II” tumors that are clinically aggressive. Patients with type II tumors 

have a five-year survival rate of less than 40 percent. 

Over the past few years, it has become evident that certain types of chromosomal and genetic 

alterations may be exploited as therapeutic targets in the treatment of certain cancers. For 

example, the drug imatinib is highly effective in the treatment of chronic myelogenous leukemia caused by a chromosome translocation. Similarly, a subset of non-small cell lung cancers 

with specific mutations that affect the catalytic domain of the epidermal growth factor receptor (EGFR) responds to the drugs gefitinib and erlotinib. An NHGRI team of investigators aims 

to identify the genetic alterations that cause serous and clear-cell tumors of the endometrium 

en route to developing new therapies for type II endometrial cancers. 

Towards that end, the research group is using high-density, single-nucleotide polymorphism 

genotyping to identify genome-wide copy-number changes and other genetic events in type 

II endometrial tumors. Parallel studies include extensive collaborations with the NIH Intramural Sequencing Center for performing mutational screens of all exons that encode the 

catalytic domains of 90 known tyrosine kinases. In addition, these efforts include searching 

for structural chromosomal alterations in endometrial tumors. Once specific genetic alterations are found to be associated with tumor development, more extensive examination of the 

clinicopathologic features of mutation-harboring tumors will be performed in an attempt to 

implicate individual genes or functional pathways that could be targeted for therapeutic 

intervention. (NHGRI) 

52
Endometrial Cancer and HNPCC 

An inherited susceptibility to endometrial cancer is usually associated with increased risk for 

hereditary nonpolyposis colorectal cancer (HNPCC). In fact, endometrial cancer is the second most common form of malignancy diagnosed in women with HNPCC. Susceptibility to 

endometrial cancer is also associated with an increased risk for Cowden syndrome, which first 

produces symptoms in the late twenties and causes multiple noncancerous growths called 

hamartomas on the skin and mucous membranes. Cowden syndrome is also linked to the 

development of breast, thyroid, and endometrial malignancies. There are a few families that 

lack either the clinical manifestations or molecular characteristics of HNPCC or Cowden syndrome, yet still have a clustering of endometrial cancer cases, which suggests a tissue-specific 

etiology. It is possible that predisposition to endometrial cancer in these families is linked to 

one or more mutations that have varying risk, rather than a single mutation that always results 

in disease. 

In an effort to learn about the influence of genetic education, counseling, and the option of 

genetic testing on psychological and behavioral outcomes in individuals at risk for inherited 

HNPCC, another NHGRI research project explores how patients perceive their risk of developing cancer, and monitors the influence of education and counseling on mood, behavior, and 

family relationships. (NHGRI) 

LUNG CANCER 

Smokefree Women 

The popular Smokefree.gov Web site has spun off a new section, Smokefree Women 

(http://women.smokefree.gov) and a companion Facebook page with information, tools, 

and discussion forums specifically developed to help female smokers quit. Women who 

smoke experience the same health hazards as men but they also face hazards unique to 

women, including endangering the life and health of a developing child if they smoke during 

pregnancy. The new site focuses on helping women integrate smoking cessation into daily 

life and family matters to help women stay smokefree. It was designed with the knowledge 

that different women need different resources to quit. 

The Web site and Facebook page contain interactive features, as well as tools that users 

can download to their personal Facebook profiles. For example, the “Talk to an Expert” feature allows users to receive information and advice about quitting smoking through real-time 

telephone-based or online LiveHelp messaging with an NCI smoking cessation counselor. A 

step-by-step Quit Guide is also provided, and the “Topics that Interest You” section includes 

information on smoking and pregnancy, depression, weight management, and relationships. 

Smokefree Women was developed by the Tobacco Control Research Branch in NCI’s Division 

of Cancer Control and Population Sciences, with assistance from CDC, Health Canada, the 

American Legacy Foundation, the Robert Wood Johnson Foundation, the American Cancer 

Society, and NCI’s Office of Communications and Education. (NCI) 

53
Chronic Diseases and Conditions in Women 

Stressed-Out DNA 

Numerous studies have demonstrated links between chronic stress and poor health, including 

cardiovascular disease and diminished immune function, but scientists are not sure why. 

Elizabeth Blackburn, Ph.D., who shared in the 2009 Nobel Prize in Physiology or Medicine, 

has investigated the hypothesis that stress impacts health by modulating the rate of cellular 

aging. She and collaborators have provided evidence that psychological stress—both perceived stress and chronicity of stress—is significantly associated with higher oxidative stress, 

lower telomerase activity, and shorter telomere length, which are known determinants of cell 

senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal 

women. Women with the highest levels of perceived stress have telomeres shorter on average 

by the equivalent of at least one decade of additional aging compared with low-stress women. 

These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases. (NIGMS) 

Reference: 

Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA. 2004 Dec 

7;101(49):17312-5. 

DIABETES 

Prevention or Delay of Type 2 Diabetes 

The Diabetes Prevention Program (DPP) randomized clinical trial demonstrated for the first 

time that type II diabetes can be prevented or delayed in women and men through intensive lifestyle intervention to induce modest weight loss. Treatment with an oral diabetes 

medication (metformin) was also effective. Further, both strategies are effective in women 

with a history of gestational diabetes, who are at greatly increased risk of developing diabetes after pregnancy. A ten-year follow-up study has demonstrated sustained benefits of the 

DPP. (NIDDK) 

References: 

Knowler WC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention 

or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403. 

Diabetes Prevention Program Research Group, Knowler WC, et al. 10-year follow-up of 

diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. 

Lancet. 2009 Nov 14;374(9702):1677-86. 

54
Gestational Diabetes 

Gestational diabetes mellitus (GDM) affects at least 200,000 pregnancies in the United 

States each year (7 percent).2 Having GDM can lead to large babies, birth injuries, and other 

pregnancy and delivery complications. However, research has shown that the effects of GDM 

last long past pregnancy. Women with a history of GDM have a 40 to 60 percent risk of 

developing diabetes, mostly type II diabetes, in the five to ten years after delivery. Moreover, 

the children of GDM-affected pregnancies are at greatly increased risk of future obesity and 

type II diabetes. For girls born to GDM pregnancies, this may increase their risk of having or 

developing diabetes while pregnant themselves, perpetuating diabetes health risks through 

future generations. 

To address this important health issue for women and their families, ORWH and the 

National Diabetes Education Program (NDEP) have partnered to significantly expand a 

GDM outreach and awareness initiative. Jointly sponsored by NIDDK and CDC with over 

200 public and private partners, NDEP seeks to reduce the burden of diabetes in the United 

States by facilitating adoption of proven approaches to prevent or delay the onset of diabetes and its complications. Since 2003, NDEP has been conducting a national, multicultural 

campaign called “Small Steps. Big Rewards. Prevent type 2 Diabetes” to disseminate the positive results of the landmark Diabetes Prevention Program (DPP) clinical trial—that type II 

diabetes can be prevented or delayed in people at high risk through lifestyle change or use 

of the medication metformin. The campaign employs materials tailored to specific high-risk 

audiences, including women with a history of GDM. ORWH provided funding to facilitate 

recruitment of women with a history of GDM into the DPP trial, enabling DPP researchers 

to determine that both trial interventions were highly and equally effective in these women, 

who were at even greater risk of developing diabetes than other high risk, prediabetic 

women enrolled in the trial. 

Now, ORWH has joined NDEP to expand and extend the reach of the tailored GDM campaign. Called “It’s Never Too Early To Prevent Diabetes. A Lifetime of Small Steps for a 

Healthy Family,” goals of the expanded campaign are to decrease the incidence of diabetes 

among women with a history of GDM, increase the awareness of health risks among affected 

families, and improve the reach of information and delivery of health care professional counseling regarding future health risks and the importance of adopting and maintaining healthy 

behaviors among these families. Through this effort, ORWH and NDEP hope to see the DPP 

results translated into positive health outcomes for women who have had GDM and their 

families. (NIDDK) 

2 Recent data from the NIH-supported Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study 

have shown that pregnancy complications occur at glucose levels lower than those currently used for 

gestational diabetes diagnosis, which in turn has led to recommendations to change the diagnostic 

definition of gestational diabetes. This change would potentially increase the burden of gestational 

diabetes to nearly 18 percent of pregnancies. These recommendations are currently under consideration. 

(International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International 

Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and 

classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-82.) 

55
Diabetes and Maternal Health 

The University of Oklahoma Center for American Indian Diabetes Health Disparities (OCAIDHD) 

aim to reduce and eventually eliminate the excess mortality, morbidity, and quality of life and 

culture lost due to diabetes. The primary impact of the Center focuses on diabetes, maternal 

health, infant mortality, and obesity. The OCAIDHD confronts health disparities by focusing the 

expertise of a multidisciplinary, multicollege team of diabetes researchers on specific biological, 

physiological, behavioral, and cultural stressors of the disease in studies such as 1) Early Markers 

of Preeclampsia in American Indians with Type 2 Diabetes, 2) Insulin Resistance and Glucocorticoid 

Treatment of Inflammatory Diseases of High Prevalence Among AI, and 3) American Indian 

Diabetes Beliefs and Practices: Maternal Care, Infant Mortality, and Adherence. (NCMHD) 

EyE DISEASE 

Age-Related Macular Degeneration 

Studies show that the incidence of age-related macular degeneration (AMD) continues to rise 

in the population as the result of the increasing percentage of elderly persons, with women 

at 50 percent greater risk than men. A study looking at AMD in women participating in the 

Nurses’ Health Study indicated a preliminary association between AMD and use of menopausal 

hormone therapy after menopause. These findings suggest a role for estrogen in the pathogenesis of AMD that requires further research in specific early and late signs of disease. (NEI) 

Reference: 

Cho E, Seddon JM, Rosner B, Willett WC, Hankinson SE. Prospective study of intake of fruits, 

vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol. 

2004 Jun;122(6):883-92 

Optic Neuritis 

The Optic Neuritis Treatment Trial (ONTT) and the Longitudinal Optic Neuritis Study (LONS) 

showed that intravenous corticosteroids delay the short-term progression of optic neuritis, an 

acute, debilitating inflammation of the optic nerve primarily affecting women with multiple 

sclerosis. This study also demonstrated that the presence of lesions on the brain on MRI scans 

performed at the time optic neuritis was diagnosed was the single most important predictor 

of the development of multiple sclerosis within five years. (NEI) 

References: 

Beck RW, et al. High- and low-risk profiles for the development of multiple sclerosis within 

10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol. 

2003 Jul;121(7):944-9. 

Beck RW, Gal RL, et al. Visual function more than 10 years after optic neuritis: experience of 

the optic neuritis treatment trial. Am J Ophthalmol. 2004;137(1):77-83. 

Beck RW, Smith CH, Gal RL, et al. Neurologic impairment 10 years after optic neuritis. Arch 

Neurology. 2004;61(9):1386-9. 

56
Optic Neuritis Study Group. Long-term brain magnetic resonance imaging changes after 

optic neuritis in patients without clinically definite multiple sclerosis. Arch Neurology. 

2004;61(10):1538-41. 

Keratoconus 

The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study provided evidence 

demonstrating an association between corneal scarring and decreased vision in keratoconus, 

which is more common in women than in men. This association may be linked to wearing 

contact lenses, suggesting that modifying lens fit can reduce this risk factor. (NEI) 

Reference: 

Barr JT, Wilson BS, Gordon MO, Rah MJ, Riley C, Kollbaum PS, Zadnik K; CLEK Study Group. 

Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. Cornea. 2006 Jan;25(1):16-25 

Idiopathic Intracranial Hypertension 

The Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC) is organizing 

a clinical study on idiopathic intracranial hypertension (IIH), a neuro-ophthalmology-related 

disease that occurs predominantly in women. The objective is to provide a unique opportunity 

to recruit and study statistically significant numbers of hard-to-find patients in order to evaluate different diagnostic and treatment options. (NEI) 

Reference: 

Kupersmith MJ, Miller N, Balcer L, Gordon L, Wall M, Keltner J, Friedman D, Feldon S, McDermott M, Kieburtz K. The Neuro-Ophthalmology Research Disease Investigator Consortium 

(NORDIC). J Neuroophthalmol. 2009 Sep; 29(3):259-61. 

HEART DISEASE 

Causes and Symptoms of Coronary Heart Disease in Women 

The Women’s Ischemia Syndrome Evaluation (WISE), a multicenter study initiated in 1996, 

has greatly increased understanding about coronary heart disease (CHD) in women and 

about gender-specific symptoms, risk factors, and pathology. The study enrolled and studied over 900 women who had symptoms of CHD (e.g., chest pain, shortness of breath) and 

were referred for diagnostic angiography. It found that approximately 50 percent of enrollees 

did not, in fact, have blockages in their large coronary arteries, yet many of them continued to experience debilitating symptoms or went on to have heart attacks. Microvascular 

dysfunction (impaired functioning of the small arteries of the heart, which is generally not 

detected by angiography) was often associated with the ischemia experienced by this large 

group of women. These findings indicate that CHD risk factors should be addressed aggressively in women with symptoms, even in the absence of a positive angiogram, and that better 

approaches to evaluate cardiac ischemia in women should be developed and used. (NHLBI) 

57
Reference: 

A special supplement to the Journal of the American College of Cardiology on CHD in women 

(Volume 47, Issue 3, Supplement 1, Pages S1-S72, February 7, 2006) included a number of 

papers from the WISE. 

The Jackson Heart Study: Epidemiology of Cardiovascular Disease in 

African-American Women 

The Jackson Heart Study is the largest single-site, prospective, epidemiologic investigation of 

cardiovascular disease among African-Americans ever undertaken. It is a population-based 

longitudinal cohort study. The Jackson Heart Study exemplifies a unique collaborative model 

among Jackson State University, Tougaloo College, the University of Mississippi Medical Center, the Jackson community, and NIH to discover and test best practices for eliminating health 

disparities. Since 1998, NCMHD has worked with NHBLI to initiate the study and, more recently, 

assess success in meeting milestones, including ensuring adequate participation by key stakeholders and advice on scientific direction, including the identification of genetic, biological, 

and environmental risk factors in African-American women. (NCMHD) 

Vitamin E and Aspirin Have Little Protective Effect on the Cardiovascular 

System in Women 

The Women’s Health Study found that low-dose aspirin and vitamin E supplements play a 

minor role, if any, in protecting women from cardiovascular disease (CVD). Aspirin use did 

not prevent first heart attacks or CVD deaths. It did, however, reduce strokes by 17 percent in 

the overall study cohort and lower the risk of major CVD events by 26 percent among women 

who were 65 years of age or older. The study also showed that vitamin E supplementation 

had no effect on heart attacks, strokes, or total deaths and—with regard to another hypothesized benefit—did not reduce rates of breast, lung, colon, or other cancers. NIH continues 

to recommend that women focus on other well-proven approaches for reducing their risk of 

heart disease and stroke—eating healthfully; engaging in regular physical activity; maintaining a healthy weight; abstaining from smoking; and controlling high cholesterol, high blood 

pressure, and diabetes. (NHLBI) 

References: 

Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A 

randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in 

women. N Engl J Med. 2005 Mar 31;352(13):1293-304. 

Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. 

Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health 

Study: a randomized controlled trial. JAMA. 2005 Jul 6;294(1):56-65. 

Women’s Cholesterol Levels Vary with Phase of Menstrual Cycle 

In recent data, NICHD researchers have shown that women and their physicians need to 

consider the phase of a women’s menstrual cycle when measuring cholesterol. In an indepth study assessing blood samples taken from healthy women between 18 and 44 years 

of age over two menstrual cycles, researchers showed that women’s cholesterol levels 

58
correspond with monthly changes in estrogen levels. On average, the total cholesterol level 

of the women in the study varied 19 percent over the course of the menstrual cycle. A small 

subset of obese women over age 40 showed greater fluctuation in cholesterol levels during 

their cycles than did the rest of the group. While previous studies have shown that taking drugs that contain estrogen—oral contraceptives or menopausal hormone therapy—can 

affect cholesterol levels, other studies examining the effects of naturally occurring hormone levels on cholesterol have been inconclusive. The researchers found that as the level 

of estrogen rises, high-density lipoprotein (HDL) cholesterol also rises, peaking at the time 

of ovulation. HDL cholesterol is believed to be protective against heart disease. In contrast, 

total cholesterol and low-density lipoprotein (LDL) cholesterol levels—as well as another 

form of blood fat known as triglycerides—declined as estrogen levels rose. The decline 

was not immediate, beginning a couple of days after the estrogen peak at ovulation. Total 

cholesterol, LDL cholesterol, and triglyceride levels reached their lowest just before menstruation began. This finding lays the groundwork for clarifying the optimal point in the 

cycle for doctors to measure women’s cholesterol levels and for helping to develop standardized procedures for measuring cholesterol in premenopausal women and determining 

their heart disease risk. (NICHD) 

Women and the Subtle Symptoms of a Heart Attack 

A study assessed the symptoms experienced by women who had suffered a heart attack in 

the previous four to six months. Virtually all of the women reported having early symptoms 

within the weeks prior to their attack, the most common being unusual fatigue and sleep 

disturbance. Less than a third of the women reported any early warning signs involving 

chest pain or discomfort, the signs most commonly associated with a heart attack. Likewise, 

the acute symptoms experienced by women during the attack included shortness of breath, 

weakness, and fatigue, but, in contrast with men, fewer than half of the women reported 

some degree of pressure, pain, or tightness of the chest during the critical time of attack 

onset. (NINR) 

Reference: 

McSweeney JC, Cody M, O’Sullivan P, Elberson K, Moser DK, Garvin BJ. Women’s early warning 

symptoms of acute myocardial infarction. Circulation. 2003;108(21):2619-23. 

Long-term Effects of a Multiple Health Behavior Intervention for 

Postmenopausal Women 

Postmenopausal women with type II diabetes are at high risk for heart disease. The Mediterranean Lifestyle Program, an intervention featuring a weekend retreat followed by 

regular meetings over 24 months to enhance healthful eating, physical activity, and stress 

management, and to support behaviors, was undertaken with 279 women. At five years 

postintervention, long-term analyses indicated that significant improvements made in the 

targeted behaviors during the active treatment phase of the study (up to 24 months) were 

partially maintained during the nontreatment phase of the study. Overall, cardiac risk factors decreased and women maintained dietary behavior and stress management levels for 

the entire follow-up period, and physical activity levels remained significantly higher for the 

first year of follow-up. These results suggest that sustained health behavior improvement is 

59
possible with a moderate-intensity group-based intervention, but that additional support may 

be needed to sustain all of the desired program effects for the long term. Funding for the 

research was provided by NHLBI and OBSSR. (OBSSR) 

Reference: 

Toobert DJ, Strycker LA, et al. Seven-year follow-up of a multiple-health-behavior diabetes 

intervention. Am J Health Behav. 2010 Nov-Dec;34(6):680-94. 

Studies of Metabolic Syndrome among Native Hawaiians, Alaska Natives, 

and Pacific Islanders 

The NCMHD Center for Native and Pacific Health Disparities Research at the University of 

Hawaii provides a regional focal point for research, research training, and community engagement aimed at cardiometabolic health and health disparities among Native Hawaiians (NH), 

Alaska Natives (AN), and other Pacific Islanders (PI) including Filipinos, Samoans, and Tongans, among other NH and PI communities. The Center conducts a Metabolic Syndrome study, 

an epidemiological study involving Filipino, NH, and Samoan youth. 

A novel community-based participatory research project called The Partnerships for Improving 

Lifestyle Interventions (PILI) has been formed between five community groups, the medical 

school, and the state department of health to focus on reducing and eliminating obesity health 

disparities. It is anticipated that women will constitute 80 percent of the participants in this 

study. Community engagement projects in Hawaii and California will assess optimal strategies 

for health information dissemination and participation among NH, AN, and PI communities to 

improve cardiometabolic health and eliminate health disparities. (NCMHD) 

Cardiovascular Disease Risk Factors and 25-Hydrocyvitamin D Serum Levels 

Researchers at the NCMHD Center of Excellence, established between the Charles Drew University of Medicine and University of California at Los Angeles, analyzed secondary data from 

the Third National Health and Nutrition Examination Survey (NHANES) to examine the association between serum levels of 25-hydroxyvitamin D and select cardiovascular disease factors 

in U.S. adults. Findings showed lower levels of 25-hydroxyvitamin D in women, elderly persons, 

racial/ethnic minorities, and participants with obesity, hypertension, and diabetes mellitus. 

(NCMHD) 

OBESITy 

Prevention of Obesity in Girls 

Results from the NHLBI Growth and Health Study—an observational study that followed 

cohorts of white and black girls from childhood to early adulthood—highlight the importance 

of teaching girls as young as age 9 about behaviors to maintain a healthy weight. Rates of 

overweight increased through adolescence from 7 percent to 10 percent among white girls 

in the study and from 17 percent to 24 percent among black girls, with the greatest jump in 

weight gain occurring at ages 9 to 12 years. Girls who were overweight during childhood were 

60
11 to 30 times more likely to be obese in young adulthood. Moreover, overweight was significantly associated with elevated systolic and diastolic blood pressures and detrimental levels of 

high-density lipoprotein cholesterol and triglycerides. The findings underscore that efforts to 

reduce cardiovascular disease risk in women should begin early in life. (NHLBI) 

Reference: 

Thompson DR, Obarzanek E, Franko DL, Barton BA, Morrison J, Biro FM, Daniels SR, StriegelMoore RH. Childhood overweight and cardiovascular disease risk factors: the National Heart, 

Lung, and Blood Institute Growth and Health Study. J Pediatr. 2007 Jan;150(1):18-25. 

Behavioral Modifications for Reducing Obesity in African-American Women 

The Uniform Services University (USU) Center for Health Disparities Research, a partnership 

between USU and the University of Maryland, Eastern Shore, conducts research on long-term 

behavioral modification aimed at reducing and preventing obesity among African-American women and applies the results of this research experience toward building a program on 

cardiovascular disease and the metabolic syndrome, both of which disproportionately affect 

minority populations. Research includes issues related to lifestyle and health, health care 

access, health status, and health disparities. The Healthy Lifestyles among African-American 

Women through Weight Loss and Exercise project is exploring ways for women within faithbased communities to sustain weight reduction and maintenance efforts using different 

exercise regimes and different behavioral therapies. The results from the successful treatment 

combination could be applicable, with the appropriate cultural modification, to faith-based 

groups from different racial and ethnic groups. The long-term expectation for this project is 

a decrease in the risk and incidence of obesity and associated conditions (e.g., hypertension, 

diabetes, metabolic syndrome, and cardiovascular disease). (NCMHD) 

Cultural Attitudes towards Weight, Diet, and Physical Activity in 

African-American Girls 

The Carolina-Shaw Partnership for the Elimination of Health Disparities and the University of North Carolina published findings on NCMHD cofunded research on cultural attitudes 

toward weight, diet, and physical activity among overweight African-American girls. The study 

examined attitudes and perceptions toward weight, diet, and physical activity among AfricanAmerican youth, and particularly among young African-American females. Weight and body 

size preferences were found to be primarily determined by the individual and her immediate social circle and were less influenced by opinions of those outside of the social circle. Food 

choices depended on texture, taste, appearance, and context more than on nutritional value. 

Engagement in recreational physical activity was influenced by time constraints from school 

and extracurricular activities and by neighborhood safety. Celebrities were not perceived as 

role models for diet and physical activity habits. The findings imply that perceptions of weight 

and healthy lifestyle behaviors are largely determined by environmental and personal influences. These factors should be considered in the development of healthy-weight interventions 

for African-American girls. (NCMHD) 

61
Educational Attainment and Metabolic Syndrome in Latina Women 

Researchers at San Diego State University recently published their research on metabolic 

syndrome in Latina women. The effects of educational attainment as a measurement of socioeconomic status and psychosocial resources on metabolic syndrome variables were examined. 

Latina women with less educational attainment reported fewer psychosocial resources and 

showed a higher risk profile on measures of blood pressure, waist circumference, and plasma 

glucose as compared with Latina women with higher educational attainment. (NCMHD) 

Obese Mothers Are Twice as Likely to Have Obese Children 

In a study conducted at the NCMHD Center of Excellence established at University of Texas, 

M.D. Anderson Cancer Center, researchers evaluated the relationship between the weight 

status of mothers and their children, 5-18 years old, at baseline in a cohort study of Mexican 

origin, low-socioeconomic status families residing in inner-city Houston, TX. This is highly 

relevant given that obesity is a risk factor for several chronic conditions later in life, including 

cardiovascular disease, type II diabetes, and some cancers. The study found obese mothers 

were twice as likely to have an overweight and/or at-risk-for-overweight child compared 

with normal-weight mothers. Women born in the United States were twice as likely to have 

an overweight and/or at-risk-for-overweight child compared with women born in Mexico. 

In addition, women with less than a high school education were twice as likely to have an 

overweight child compared with their more educated peers. (NCMHD) 

Obesity-Disease Risk Guidelines in Various Populations 

The Body Composition, Hormones, and Health Risk Factors in Middle-Aged Hispanic, AfricanAmerican and Caucasian Women study being conducted at the Hispanic Health Disparities 

Research Center at the University of Texas, El Paso, examines the obesity-disease risk relationship among racial/ethnic groups in the development of healthy-weight guidelines. 

Analyses include determination of body fat ranges related to dyslipidemia, hypertension, and 

elevated glucose and insulin concentrations in each group and the obesity-hormone relationship among the racial/ethnic groups. These interrelationships are critical in developing an 

understanding of the etiology of diseases. (NCMHD) 

Gender and the Effect of Obesity on Asthma 

A finding from NIAID’s Inner City Asthma Consortium suggests that obesity makes asthma 

harder to control in adolescent females but not in males. The Inner City Asthma Consortium 

studies asthma risk factors and promising therapies to reduce the severity and prevent disease 

onset among children and adolescents living in the inner city. (NIAID) 

Reference: 

Kattan M, Kumar R, Bloomberg GR, Mitchell HE, Calatroni A, Gergen PJ, Kercsmar CM, 

Visness CM, Matsui EC, Steinbach SF, Szefler SJ, Sorkness CA, Morgan WJ, Teach SJ, Gan VN. 

Asthma control, adiposity, and adipokines among inner-city adolescents. J Allergy Clin 

Immunol. 2010;125(3):584-92. 

62
Gender, Obesity, C-Reactive Protein, and Oxidative Stress 

The long-term objective of this project is to identify nutritional factors that can reduce the 

inflammatory component of obesity, a major risk factor for many chronic diseases of aging. 

Therapies to minimize obesity-related comorbidities are needed, and targeting inflammation may help slow the progression of obesity towards cardiovascular disease and insulin 

resistance. C-reactive protein (CRP) is a key marker of inflammation. Previous research has 

demonstrated that supplementation with vitamin C reduces CRP in active and passive smokers and in nonsmokers, particularly among individuals whose CRP levels place them at 

elevated risk of cardiovascular disease. NIH-supported investigators are now performing a 

clinical trial of the effects of supplementation with vitamin C on CRP levels in obese individuals. The investigators also plan to characterize the pathways through which any effect 

takes place by measuring cytokines and oxidative stress. If supplementation with vitamin C 

is effective in this population, it could offer a low-cost alternative to use of statins to reduce 

inflammation in persons without other risk factors. (ODS) 

OSTEOARTHRITIS 

Knee Osteoarthritis and Sports Injuries in Women 

Traumatic knee injury often leads to osteoarthritis (a painful condition characterized by 

cartilage degeneration) in the joint several years later. Injuries to the anterior cruciate ligament of the knee occur in girls and women who participate in high-risk sports, such as 

soccer and basketball, at a four- to sixfold greater rate than in their male counterparts. 

Researchers are beginning to appreciate that structural differences of the knee joint and 

thigh muscles, differences in the ways male and female athletes move, and other sex 

differences explain why women are more susceptible to injuries than men. They are also 

developing strategies to identify young female athletes who could benefit from interventions to prevent these injuries. (NIAMS) 

References: 

Arendt E, Dick R. Knee injury patterns among men and women in collegiate basketball and 

soccer. NCAA data and review of literature. Am J Sports Med. 1995 Dec;23(6):694-701. 

Griffin LY, Albohm MJ, Arendt EA, Bahr R, Beynnon BD, Demaio M, Dick RW, Engebretsen L, 

Garrett WE Jr, Hannafin JA, Hewett TE, Huston LJ, Ireland ML, Johnson RJ, Lephart S, Mandelbaum BR, Mann BJ, Marks PH, Marshall SW, Myklebust G, Noyes FR, Powers C, Shields C Jr, 

Shultz SJ, Silvers H, Slauterbeck J, Taylor DC, Teitz CC, Wojtys EM, Yu B. Understanding and 

preventing noncontact anterior cruciate ligament injuries: a review of the Hunt Valley II meeting, January 2005. Am J Sports Med. 2006 Sep;34(9):1512-32. 

Myer GD, Ford KR, Barber Foss KD, Liu C, Nick TG, Hewett TE. The relationship of hamstrings 

and quadriceps strength to anterior cruciate ligament injury in female athletes. Clin J Sport 

Med. 2009 Jan;19(1):3-8. 

63
Myer GD, Ford KR, Paterno MV, Nick TG, Hewett TE. The effects of generalized joint laxity 

on risk of anterior cruciate ligament injury in young female athletes. Am J Sports Med. 2008 

Jun;36(6):1073-80. 

Myklebust G, Steffen K. Prevention of ACL injuries: how, when and who? Knee Surg Sports 

Traumatol Arthrosc. 2009 Aug;17(8):857-8. 

Acupuncture Relieves Knee Pain from Osteoarthritis 

A landmark study has shown that acupuncture provides pain relief and improves function 

for people with osteoarthritis of the knee. This was the first clinical trial with sufficient rigor, 

size, and duration to show that acupuncture reduces the pain and functional impairment of 

osteoarthritis of the knee. The study results also indicated that acupuncture can serve as an 

effective addition to a standard regimen of care and improve quality of life for knee osteoarthritis sufferers. This study was funded by NCCAM and NIAMS. (NCCAM) 

Reference: 

Berman BM, Lao L, Langenberg P, Lee WL, Gilpin AM, Hochberg MC. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann 

Intern Med. 2004;141(12):901-10. 

Glucosamine plus Chondroitin Relieves Pain for Some, but Not All, 

Arthritis Patients 

The Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) found that, overall, the combination of glucosamine plus chondroitin sulfate did not provide significant relief from 

osteoarthritis pain among all study participants. However, a smaller subgroup of individuals 

with moderate-to-severe pain showed significant relief with the combined supplements. The 

trial was funded by NCCAM and NIAMS. (NCCAM) 

References: 

Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, Bradley JD, Bingham CO 3rd, 

Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe 

F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, 

Williams HJ. Glucosamine, chondroitin sulfate, and the two in combination for painful knee 

osteoarthritis. New Engl J Med. 2006;354(8):795-808. 

Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO 3rd, Harris CL, Singer NG, Bradley JD, 

Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Reda DJ, Moskowitz RW, 

Williams HJ, Clegg DO. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the Glucosamine/Chondroitin Arthritis Intervention 

Trial. Arthritis & Rheum. 2008;58(10):3183-91. 

64
The Osteoarthritis Initiative 

Because osteoarthritis affects over 27 million individuals in the United States, NIH has long 

supported research to improve methods for assessing disease onset and progression. Knee 

osteoarthritis is associated with significant pain and development of disability over time. 

People who are severely compromised have few effective treatment options other than joint 

replacement. It has long been noted that there are differences in the prevalence, incidence, 

and severity of osteoarthritis between men and women. Women have higher incidence of 

osteoarthritis of the knee, hip, and hand. Severity of disease is significantly worse in women 

and women are less willing to undergo joint replacement surgery than are men. Thus, the 

course of disease in women is associated with significant morbidity and disability. There are 

currently no disease modifying agents for the treatment of osteoarthritis. The discovery of 

osteoarthritis biomarkers—including structural characteristics that can be observed with 

MRI—could lead to identification of new treatment targets and mechanisms for shorter, more 

efficient trials of disease-modifying agents. 

The Osteoarthritis Initiative (OAI) is a multicenter, longitudinal, prospective observational 

study of knee osteoarthritis (OA) that was launched by NIH in 2002. The overall aim of the OAI 

is to develop a public-domain research resource to facilitate the scientific evaluation of biomarkers for osteoarthritis as potential surrogate endpoints for disease onset and progression. 

The goals of the OAI are to enroll approximately 5,000 subjects with risk factors for or early 

knee osteoarthritis and collect clinical and imaging data and biological specimens from these 

participants for eight years of follow-up. No details are provided here with regard to study 

startup, protocol development, or recruitment and enrollment. These details are available on 

the OAI website (www.oai.ucsf.edu/datarelease/StudyOverview.asp). 

The OAI research team consists of the following centers and their principal investigators: 

University of Maryland School of Medicine, Baltimore, and Johns Hopkins University: Marc 

Hochberg, M.D., M.P.H.; The Ohio State University, Columbus: Rebecca Jackson, M.D.; University of Pittsburgh: C. Kent Kwoh, M.D.; Memorial Hospital of Rhode Island, Pawtucket: Charles 

Eaton, M.D.; University of California, San Francisco (data coordinating center): Michael Nevitt, 

Ph.D. A Steering Committee advises on the scientific aspects of the study. The FDA provides 

a representative to serve as a liaison to the Steering Committee in an advisory manner. 

The OAI cohort of 4,796 subjects is 58 percent female and ranged in age from 45-79 at the 

time of recruitment. As of summer 2010, the entire OAI cohort has completed their baseline, 

12-, 24-, and 36-month visits. About 99 percent of the 48-month visits have been completed. 

The 60-month visit is by telephone and is approximately 71 percent complete. The 72-month 

visits are in-clinic and well under way at all sites. Eighty-four-month telephone and mail visits and 96-month in-clinic visits are planned. A subset of participants in the progression 

cohort were also seen at 18 months (n=288) or 30 months (n=494) for knee MRI, blood draw, 

65
exam, and questionnaire data to allow for analysis of change over shorter intervals. Retention 

remains high. The rate of no-contact has stabilized at 10 percent. 

Seventy-three percent of participants have a knee x-ray and 70 percent have a knee MRI for 

all five time points. Sixty-seven percent of participants are estimated to have knee x-rays and 

MRIs at all time points. Any bias regarding those who do not have an MRI will be addressed in 

the analysis. 

There are four separate NIH-funded (R01 and R21 mechanisms) ancillary studies to the OAI, 

which are well under way. One of the most recent ancillary studies addresses the effects of 

physical activity on disability progression. Physical activity is measured using an accelerometer to see whether participants who meet the recommended activity guidelines can slow 

disability progression. 

The OAI is supporting some analyses of the MRI and x-ray data, which are being annotated 

with the source and posted to the Web site. Since the preferred method for reading the MRIs 

is unclear, there are no efforts to read the MRIs for the entire cohort at this time. Selected 

readings are posted to allow researchers to test their own hypotheses for what components 

and methods of reading provide the best diagnostic variable for predicting progression. It is 

proposed that funds from the American Revitalization and Recovery Act (ARRA) will be used 

to read the OAI x-rays. Other OAI investigators are requesting supplemental funding from the 

ARRA to support ancillary studies. 

Data are released on a regular basis to OAI-online. As of June 2010, there were 1,649 registered users of OAI Online from 71 countries, with over 5,606 datasets downloaded and 232 

image sets distributed. Data are currently being released in a single bolus for the entire visit. 

Recent releases have included the 36-month questionnaire and exam data and images for the 

full cohort, as well as the 30-month questionnaire and exam data and images for a subset of 

the progression cohort. An increasing number of abstracts and papers are being produced 

from the data (see www.oai.ucsf.edu/datarelease/Publications.asp). 

This groundbreaking study is expected to advance the understanding of how modifiable and 

nonmodifiable risk factors are linked to development and worsening of knee osteoarthritis. 

These findings may in turn lead to improved strategies for prevention of disease, identification 

of novel treatment targets, and ways to prevent later-life disability. 

Funding for the OAI has been contributed by both NIH and private-sector participants. The 

private-sector funding was initially provided from Pfizer, Merck, GlaxoSmithKline, and Novartis. The Foundation for the National Institutes of Health (FNIH) has coordinated private-sector 

participation. Funding from the NIH Institutes and Centers initially included NIAMS and NIA, 

NCCAM, NCMHD, NIDCR, NIBIB, and ORWH. ORWH has been and continues to be a major 

contributor to the OAI. 

66
OSTEOPOROSIS
�

Preventing Hip Fracture Due to Osteoporosis 

Once thought to be a normal consequence of aging, hip fractures due to osteoporosis can 

be prevented. Health care providers now know that bone mineral density of the hip is one of 

the best predictors of future fractures, and that certain lifestyle changes (such as improving 

nutrition or exercising) can reduce a person’s fracture risk. Clinicians have an arsenal of bonepreserving drugs that they can prescribe; because of NIH-funded research, they understand 

how to combine the different medications to preserve bone health. These advances—along 

with other NIH-sponsored activities to improve osteoporosis prevention, diagnosis, and treatment—are having a positive effect on bone health. Specifically, the overall age-adjusted 

hospitalization rate for hip fractures among older women is decreasing (down 24.5 percent 

from 1995 until 2005), and the percent whose bone mineral density tests show that they are at 

risk of osteoporotic fractures also has decreased. (NIAMS) 

References: 

Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt 

TM. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research 

Group. N Eng J Med. 1995 Mar 23;332(12):767-73. 

Black DM, et al. The effects of parathyroid hormone and alendronate alone or in combination 

in postmenopausal osteoporosis. N Eng J Med. 2003 Sep 25;349(13):1207-15. 

Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in 

the United States. JAMA. 2009 Oct 14;302(14):1573-9. 

Looker AC, Melton LJ 3rd, Harris TB, Borrud LG, Shepherd JA. Prevalence and trends in low 

femur bone density among older US adults: NHANES 2005-2006 compared with NHANES III. 

J Bone Miner Res. 2010 Jan;25(1):64-71. 

A Reference Model to Understand Osteoporosis 

Osteoporosis is a skeletal disorder in which bones weaken due to the loss of bone mineral 

density, and the risk of fracture is increased. The disease affects both men and women of 

all ages, although women over 50 have more than twice the prevalence of low bone density 

than men. The chance of fracture increases with age. While any fracture is a serious occurrence, hip fractures are of greatest public health concern because the consequences are 

often devastating. For example, those who experience hip fractures have an increased 

risk of death during the first 12 months after the fracture. Among those who survive, many 

experience loss of mobility and may have to enter long-term care facilities. Finally, hip fractures cost more to repair than any other type of osteoporotic fracture. Current projections 

indicate that the prevalence of this disease will grow dramatically over the next decade 

from the current 10 million individuals affected, considering the aging American population. 

Osteoporosis is a complex, multifactorial disorder with multiple causes, including hormonal, 

genetic, and lifestyle-related factors. Prediction of who is at risk and who will respond to 

an intervention is, therefore, difficult and requires an understanding of the interplay of a 

67
multitude of parameters. Investigators at UCLA are developing a Bayesian Belief Network 

(BBN) model of bone density and quality at the peak of skeletal development in order to 

provide a tool for better understanding the genesis of osteoporosis. The model is based 

on quantitative data from a reference population consisting of healthy volunteers aged 

20-30 years old. The patient population to be studied suffers from chronic renal diseases 

that result in osteoporotic conditions. The BBN along with visualization tools, also under 

development, will make it easier for researchers to examine cause and effect of numerous 

variables on bone development. (NIBIB)
�

References:
�

Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab. 2010 Feb;95(2):471-8.
�

http://www.cdc.gov/nchs/data/nhanes/databriefs/osteoporosis.pdf 

Efficacy of Turmeric Extract in Prevention of Postmenopausal Osteoporosis 

The identification of a dietary supplement that effectively inhibits bone resorption could 

offer a particularly attractive approach to the prevention of postmenopausal osteoporosis, 

a disease with extremely high prevalence that is essentially irreversible yet readily preventable by early interventions that inhibit bone resorption. Recent studies in an animal model 

of arthritis have demonstrated that curcuminoid-containing turmeric extracts (C-CTEs) are 

potent inhibitors of inflammation-associated bone resorption. Because the same inflammatory pathways mediate bone loss in arthritis and in menopause, researchers have 

hypothesized that C-CTEs may be similarly efficacious in the prevention of postmenopausal 

osteoporosis. NIH-supported investigators are now exploring this hypothesis using models of surgical and natural menopause in rats. Evidence obtained in this study supporting 

(or refuting) the efficacy of turmeric dietary supplements in osteoporosis prevention and/or 

treatment will: (1) begin to help guide the public’s use of turmeric supplements for the preservation of bone health, (2) aid in the design of preclinical trials comparing the efficacy and 

identifying turmeric’s mechanism of action on bone, and (3) provide necessary information 

for the design of future clinical trials. (ODS) 

Bone Response to Soy Isoflavones in Women 

Soy protein rich in isoflavones (estrogen-like compounds) has been shown to prevent bone 

loss in ovariectomized rats, and preliminary study results suggest a bone-sparing effect of 

isoflavones in perimenopausal women. However, the long-term efficacy of isoflavones on 

bone in humans is unknown. NIH-supported investigators are currently conducting a threeyear study to establish the efficacy of isoflavone-rich soy extract in attenuating bone loss in 

postmenopausal women. This study will provide valuable data on whether isoflavones impact 

bone in early postmenopausal women and help elucidate potential mechanisms, thereby 

contributing to the understanding of isoflavones as an alternative to traditional menopausal 

hormone therapy. (ODS) 

68
Folic Acid and B Vitamins to Prevent Fracture in Women 

Prospective studies have found that women with elevated plasma homocysteine have a substantially increased risk of osteoporotic fractures, including hip fractures. Investigators are 

currently studying, within the context of an ongoing randomized trial (the Women’s Antioxidant Cardiovascular Study), whether reducing plasma homocysteine levels by dietary 

supplementation with folic acid, vitamin B6, and vitamin B12 will reduce the risk of non-spine 

fractures in women. This study will be instrumental in determining whether a safe and inexpensive nutritional intervention substantially reduces the risk of fracture and in understanding 

the mechanism of this effect. (ODS) 

Impact of a Protein Supplement on Bone Mass in Older Women 

Nutrition plays a critical role in bone health, but its role in the pathogenesis and prevention 

of bone loss is incompletely understood. Investigators have found that dietary protein is a 

major regulator of calcium homeostasis, yet its impact on skeletal health remains controversial. Increasing dietary protein is known to increase urinary calcium excretion, and a widely 

held view is that this extra calcium originates in part from bone, but recent epidemiologic 

studies have found that higher protein intakes are associated with higher (not lower) bone 

mineral density and lower (not higher) rates of bone loss. NIH-supported investigators have 

found that when dietary protein is increased in healthy women, intestinal calcium absorption 

increases significantly and accounts for almost all of the increase in urinary calcium, and that 

when women consume a high-protein diet, the percentage of urinary calcium originating from 

bone is reduced and bone turnover is also slightly reduced. The investigators are currently 

performing a clinical trial of protein supplementation in older women who typically consume a low-normal protein diet in order to assess the effects of protein supplementation on 

bone mass. This study will better inform dietary protein recommendations for optimal skeletal 

health and potentially suggest a new therapeutic approach to age-related bone loss. (ODS) 

PAIN 

Gender-Based Differences in Pain Response 

Researchers tested the effects of nalbuphine, a member of a little-used class of medications 

called kappa-opioids, on women and men after surgery for wisdom tooth extraction. They found 

that women gained relief of their postoperative pain from a moderate dose of nalbuphine, while 

both higher and lower doses had little effect when compared with a placebo. In men, only a high 

dose offered slight, short-term pain relief, while a low dose actually intensified the pain. Kappaopioids have fewer negative side effects, such as nausea, confusion, and constipation, than the 

more commonly used mu-opioids like morphine. The difference in pain perceptions and responses 

between women and men uncovered in this study was an unexpected result and revealed the 

importance of considering gender in developing pain management strategies. (NINR) 

Reference: 

Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with 

postoperative pain. Pain. 1999;83(2):339-45. 

69
Irritable Bowel Syndrome 

New Insights into the Pain Associated With Irritable Bowel Syndrome 

Researchers at a specialized center of research cofunded by ORWH and NIDDK found that 

women with irritable bowel syndrome (IBS) perceive visceral pain associated with IBS differently than do healthy volunteers, and exhibit altered brain activity responses to both pain and 

the anticipation of pain. They also found that a history of physical abuse heightens visceral 

pain responses in women with IBS. Moreover, researchers have identified sex/gender-specific 

differences in brain activity in women and men with IBS. These findings may lead to improved 

treatment strategies and outcomes for IBS-related pain. (NIDDK) 

References: 

Berman SM, Naliboff BD, Suyenobu B, Labus JS, Stains J, Ohning G, Kilpatrick L, Bueller JA, 

Ruby K, Jarcho J, Mayer EA. Reduced brainstem inhibition during anticipated pelvic visceral 

pain correlates with enhanced brain response to the visceral stimulus in women with irritable 

bowel syndrome. J Neurosci. 2008 Jan 9;28(2):349-59. 

Ringel Y, Drossman DA, Leserman JL, Suyenobu BY, Wilber K, Lin W, Whitehead WE, Naliboff 

BD, Berman S, Mayer EA. Effect of abuse history on pain reports and brain responses to aversive visceral stimulation: an FMRI study. Gastroenterology. 2008 Feb;134(2):396-404. 

Labus JS, Naliboff BN, Fallon J, Berman SM, Suyenobu B, Bueller JA, Mandelkern M, Mayer EA. 

Sex differences in brain activity during aversive visceral stimulation and its expectation 

in patients with chronic abdominal pain: a network analysis. Neuroimage. 2008 Jul 

1;41(3):1032-43. 

Temporomandibular Joint Disorders 

Temporomandibular Joint and Muscle Disorders 

Pain conditions, particularly temporomandibular joint (TMJ) and muscle disorders (TMJMDs), 

have been an active area of NIDCR-supported research for many years. Data from the 2002 

U.S. National Health Interview Survey confirm that TMJMD-type pain is 2.25 times more prevalent in women than in men. Other studies indicate that gender-based differences in pain 

conditions may be due to hormonal influences and genetic susceptibilities. In addition to clinical studies, multiple investigators supported by NIDCR have studied basic mechanisms related 

to orofacial pain. Another significant program examining new TMJMD is Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA), a prospective study of 3,200 healthy 

subjects designed to identify risk factors contributing to TMJMD onset. (NIDCR) 

References: 

Isong U, Gansky SA, Plesh O. Temporomandibular joint and muscle disorder-type pain in U.S. 

adults: the National Health Interview Survey. J Orofac Pain. 2008 Fall;22(4):317-22. 

70
Kramer PR, Bellinger LL. The effects of cycling levels of 17beta-estradiol and progesterone 

on the magnitude of temporomandibular joint-induced nociception. Endocrinology. 2009 

Aug;150(8):3680-9. 

Diatchenko L, Anderson AD, Slade GD, Fillingim RB, Shabalina SA, Higgins TJ, Sama S, Belfer 

I, Goldman D, Max MB, Weir BS, Maixner W. Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a 

common musculoskeletal pain disorder. Am J Med Genet B Neuropsychiatr Genet. 2006 Jul 

5;141B(5):449-62. 

https://www.oppera.org/ 

NIH Technology Assessment Conference: Management of Temporomandibular 

Disorders, April 29-May 1, 1996 

OMAR and the National Institute of Dental Research (now known as NIDCR) convened an 

independent panel in 1996 to assess the available scientific evidence on the management of 

temporomandibular disorders (TMD). The panel found significant problems with diagnostic 

classifications of TMD and recommended that validated diagnostic methods be developed. 

The panel further concluded that the preponderance of the data did not support the superiority of any method for initial management of most TMD problems. Moreover, the superiority 

of such methods to placebo controls or no treatment controls was undetermined. Because 

most individuals experience improvement or relief of symptoms with conservative treatment, 

the panel concluded that the vast majority of TMD patients should receive initial management using noninvasive and reversible therapies. They believed surgical intervention should 

be considered in the small percentage of patients with persistent and significant pain and 

dysfunction who show evidence of pathology, or internal derangement of the temporomandibular joint, and for whom more conservative treatment has failed. An identified area of 

future research is the underlying etiology behind the gender difference inherent in this disorder (with an observed predominance in women in their 30s and 40s). (OMAR) 

URINARy INCONTINENCE 

Weight Loss in Overweight and Obese Women Reduces Urinary Incontinence 

The Program to Reduce Incontinence by Diet and Exercise (PRIDE) clinical trial demonstrated 

that weight loss significantly reduces episodes of urine leakage in overweight and obese 

women who experience incontinence. Evidence of this additional health benefit of weight loss 

expands the options physicians and their patients can consider for treating incontinence in 

women. (NIDDK) 

Reference: 

Subak LL, et al. Weight loss to treat urinary incontinence in overweight and obese women. 

N Engl J Med. 2009 Jan 29; 360(5):481-90. 

71
Sling Surgery Is More Effective Than Burch for Bladder Control in Women 

The Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr), conducted by NIDDK’s 

Urinary Incontinence Treatment Network, found that a sling procedure for stress urinary 

incontinence (SUI) helps more women achieve dryness than the Burch technique. This rigorous trial also provided insights into surgical therapy outcomes, such as differences in side 

effects from the two procedures, that will help women with SUI and their health care providers make better-informed treatment decisions. (NIDDK) 

Reference: 

Albo ME, et al. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med. 2007 May 24; 356(21):2143-55. 

72
Neuroscience and Brain-Based Disorders
�

NEUROSCIENCE AND THE FEMALE BRAIN 

Sexual Differentiation of the Brain and Behavior 

Sex Chromosomes Affect Sexual Differentiation of the Brain and Behavior 

Research on mammalian sexual differentiation exploded in the second half of the 20th 

century. This work built on an “organizational-activational” hypothesis which posited that 

gonadal hormone actions during critical periods of development were responsible for sex 

differences in brain structure and in behavioral responses to gonadal hormones during 

adulthood (often reproductive behavioral responses). More recently, however, the ability to 

manipulate the genome independently of gonadal hormones has changed the understanding of sexual differentiation. Specifically, studies using transgenic mice have demonstrated 

that many sexually dimorphic phenotypes—ranging from the molecular to the behavioral— 

are caused primarily by differences in the sex (i.e., X and Y) chromosomes, independent of 

or in addition to, the actions of hormones (reviewed by Arnold in 2009). Examples of these 

primary sex chromosome effects include sexual dimorphisms in the response to nociceptive 

stimuli, habit formation, and autoimmune responses and disease progression in mouse models of multiple sclerosis and systemic lupus erythematosus. This more comprehensive view of 

sexual differentiation has important implications for general understanding of sex differences 

in health and disease. Funding for this research was provided by NICHD, NIDA, NIDDK, and 

NINDS. (OBSSR and NIMH) 

References: 

Arnold AP. The organizational–activational hypothesis as the foundation for a unified theory 

of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55(5):570-8. 

Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex 

differences in the brain and other tissues? Front Neuroendocrinol. 2009 Jan;30(1):1-9. 

Phoenix CH, Goy RW, Gerall AA, Young WC. Organizing action of prenatally administered 

testosterone propionate on the tissues mediating mating behavior in the female guinea pig. 

Endocrinology. 1959 Sep;65:369-82. 

Quinn JJ, Hitchcott PK, Umeda EA, Arnold AP, Taylor JR. Sex chromosome complement 

regulates habit formation. Nat Neurosci. 2007 Nov;10(11):1398-400. 

73
Females Fight Differently 

Most studies of aggression, in humans or animal models, focus on males. However, a Harvard 

Medical School team discovered that Drosophila (fruit fly) females fight, and that the circumstances that trigger aggression, the flies’ fighting behaviors, and the effects of being a winner 

or loser of previous fights are all sex-specific. Subsequently, the team demonstrated that they 

can induce male flies to fight like females, and vice versa, by manipulating expression of sex 

determination genes in the brain. Recently, the team made a counterintuitive discovery: genetically feminizing a subset of the neurons in the brain, during development, makes male flies 

significantly more aggressive. Given the similarity in human and fly brains in terms of how they 

develop and function, it would be surprising if female aggression in the two species shared 

no common substrates. Accordingly, the team’s studies may illuminate efforts to determine 

the biological basis for aggression in women and identify environmental, developmental, and 

social factors that affect women’s aggression. (NIGMS) 

References: 

Nilsen SP, Chan YB, Huber R, Kravitz EA. Gender-selective patterns of aggressive behavior in 

Drosophila melanogaster. Proc Natl Acad Sci USA. 2004 Aug 17;101(33):12342-7. 

Chan YB, Kravitz EA. Specific subgroups of FruM neurons control sexually dimorphic patterns of 

aggression in Drosophila melanogaster. Proc Natl Acad Sci USA. 2007 Dec 4;104(49):19577-82. 

Mundiyanapurath S, Chan YB, Leung AK, Kravitz EA. Feminizing cholinergic neurons in a male 

Drosophila nervous system enhances aggression. Fly (Austin). 2009 Jul-Sep;3(3):179-84. 

Stroke 

Estrogen Replacement Does Not Protect Against Recurrent Stroke 

Results of a clinical trial evaluating the impact of menopausal hormone therapy on recurring 

stroke in postmenopausal women were announced in October 2001. The Women’s Estrogen 

for Stroke Trial (WEST), supported by NINDS, was the first randomized, controlled clinical trial 

of estrogen therapy for secondary prevention of cerebrovascular disease. Investigators found 

that estrogen menopausal hormone therapy did not reduce the risk of stroke or death in postmenopausal women who had already had a stroke or transient ischemic attack and, therefore, 

suggested that this therapy should not be prescribed. (NINDS) 

Reference: 

Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogenreplacement therapy after ischemic stroke. N Engl J Med. 2001 Oct 25;345(17):1243-9. 

Preeclampsia Increases Risk of Stroke over Lifetime 

Stroke in pregnancy is associated with several factors including preeclampsia, a serious complication of pregnancy marked by high blood pressure, weight gain, and protein in the urine. 

An analysis of the data from the Stroke Prevention in Young Women Study (a large NINDSfunded clinical study of the genetic and environmental risk factors for ischemic stroke) showed 

74
that, over their lifetime, women with a history of preeclampsia are 60 percent more likely to 

have a nonpregnancy-related stroke. A history of preeclampsia should therefore be considered 

a risk factor for stroke. (NINDS) 

Reference: 

Brown DW, Dueker N, Jamieson DJ, Cole JW, Wozniak MA, Stern BJ, Giles WH, Kittner SJ. 

Preeclampsia and the risk of ischemic stroke among young women: results from the Stroke 

Prevention in Young Women Study. Stroke. 2006 Apr;37(4):1055-9. 

Women with Visual Aura during Migraine Are at Higher Risk for 

Ischemic Stroke 

Researchers from the Stroke Prevention in Young Women Study (SPYWS), a large clinical 

study of the genetic and environmental risk factors for ischemic stroke funded by NINDS, 

examined clinical features of migraine that place women at a greater risk for stroke. This study 

showed that women who frequently had a visual aura during migraine had 1.5 greater odds of 

having an ischemic stroke than women without migraine or women with migraines and without auras. Furthermore, the combined use of oral contraceptives and smoking placed women 

with visual auras during migraine at the highest risk for stroke, increasing the odds of suffering ischemic stroke by sevenfold compared with women with visual aura that did not smoke 

or use oral contraceptives. This study was also supported in part by the VA, CDC, ORWH, NIA, 

and NCRR. (NINDS) 

Reference: 

MacClellan LR, Giles W, Cole J, Wozniak M, Stern B, Mitchell BD, Kittner SJ. Probable migraine 

with visual aura and risk of ischemic stroke: the stroke prevention in young women study. 

Stroke. 2007 Sep;38(9):2438-45. 

Strong Relationship between Smoking and Stroke in Young Women 

While cigarette smoking is a known risk factor for ischemic stroke (the type caused by blood 

clots), the relationship between cigarette dose and stroke risk had not been examined in a 

young (15- to 50-year-old), ethnically diverse population of women. Researchers from the 

Stroke Prevention in Young Women Study (SPYWS), a large clinical study of the genetic and 

environmental risk factors for ischemic stroke funded by NINDS, found a strong relationship 

between the number of cigarettes smoked per day and the probability of ischemic stroke in 

young women. The study also found that black women were more likely than white women to 

smoke, therefore placing them at greater risk. The findings support the need to target smoking as a preventable and modifiable risk factor for cerebrovascular disease in young women. 

This study was also supported in part by the VA, CDC, ORWH, NIA, and NCRR. (NINDS) 

Reference: 

Bhat VM, Cole JW, Sorkin JD, Wozniak MA, Malarcher AM, Giles WH, Stern BJ, Kittner SJ. Doseresponse relationship between cigarette smoking and risk of ischemic stroke in young women. 

Stroke. 2008 Sep;39(9):2439-43. 

75
Substance Abuse 

Sex and Gender Differences in Drug Addiction 

Research supported by NIDA has shown that antecedents, consequences, and mechanisms 

of drug addiction differ in males and females, which in turn often affects treatment and prevention outcomes differently for males and females. Further, mounting evidence shows that 

animal models of addiction based solely on males are incomplete and ignore both the effects 

of gonadal hormones and sexual dimorphism in the brain. (NIDA)
�

References:
�

Wetherington CL. Sex-gender differences in drug abuse: a shift in the burden of proof? Exp 

Clin Psychopharmacol. 2007 Oct;15(5):411-7.
�

Wetherington CL. Sex differences and gonadal hormone influences in drug addiction and 

sexual behavior: progress and possibilities. Horm Behav. 2010;58(1):2-7
�

Gender Differences in Response to Nicotine Replacement 

Men and women respond differently to nicotine replacement therapy, highlighting the 

importance of including gender analyses in medication trials for substance abuse. A metaanalysis of 14 placebo-controlled trials of nicotine patch therapy for smoking cessation 

revealed poorer long-term (6 months) outcomes in women than in men. The odds ratio 

for quitting with the patch versus placebo was 2.20 for men and 1.61 for women. Reasons 

underlying this differential response may include that (a) women metabolize nicotine more 

quickly than men, potentially decreasing the effectiveness of nicotine replacement therapy 

and (b) smoking-related cues play a larger role in motivating women to smoke than they do 

men, a gender-sensitive relapse factor that may need to be addressed to optimize treatment 

effectiveness. (NIDA) 

References: 

Perkins KA, Scott J. Sex differences in long-term smoking cessation rates due to nicotine 

patch. Nicotine Tob Res. 2008;10(7):1245-50. 

Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A, Benowitz N. Nicotine 

metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol 

Ther. 2006;79(6):600-8. 

Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd. Female sex and oral contraceptive 

use accelerate nicotine metabolism. Clin Pharmacol Ther. 2006;79(5):480-8. 

Perkins KA, Gerlach D, Vender J, Grobe J, Meeker J, Hutchison S. Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine Tob Res. 

2001;3(2):141-50. 

76
Gender Differences in the Abuse of Prescription Drugs 

Gender is a key factor in understanding the problem of prescription drug abuse and addiction. 

While the prevalence of prescription drug abuse overall in the United States is higher among 

males than among females, young girls (12- to 17-year-olds) exceed boys in the nonmedical use of all psychotherapeutics, including pain relievers, tranquilizers, and stimulants, and 

females in general show a faster progression to dependency. Growing evidence suggests that, 

compared with males, females’ motivations to abuse prescription drugs tend more toward 

self-“improvement” (e.g., weight loss, performance enhancement), self-medication, and coping than to get high. These differences demand research and interventions that take gender 

into account. (NIDA) 

References: 

Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ. Illicit use of specific prescription 

stimulants among college students: prevalence, motives, and routes of administration. 

Pharmacotherapy. 2006;26(10):1501-10. 

McCabe SE, Cranford JA, Boyd CJ, Teter CJ. Motives, diversion and routes of administration 

associated with nonmedical use of prescription opioids. Addict Behav. 2007;32(3):562-75. 

Greenfield SF, Back SE, Lawson K, Brady KT. Substance abuse in women. Psychiatr Clin North 

Am. 2010 Jun;33(2):339-55. 

Lynch WJ. Acquisition and maintenance of cocaine self-administration in adolescent rats: 

effects of sex and gonadal hormones. Psychopharmacology. 2008;197(2):237-46. 

Sex Differences in Vulnerability to Rewarding Effects of Drugs of Abuse 

Preclinical studies show that females are more vulnerable than males to the rewarding effects 

of abused drugs at all stages of drug abuse: initiation, maintenance, escalation, bingeing, 

extinction of drug-seeking behavior (when drug access is removed), and relapse. These 

sex differences remain even in the absence of circulating gonadal hormones. Studies also 

reveal sex differences in neurotransmitter systems underlying drug reward. Researchers 

are beginning to investigate how gonadal hormones affect these behavioral outcomes and 

neurotransmitter systems compared with independent sex chromosomal effects on brain 

organization, neurochemistry, and function. (NIDA) 

References: 

Evans SM, Foltin RW. Does the response to cocaine differ as a function of sex or hormonal 

status in human and non-human primates? Horm Behav. 2010;58(1):13-21. 

Kuhn C, Johnson M, Thomae A, Luo B, Simon SA, Zhou G, Walker QD. The emergence 

of gonadal hormone influences on dopaminergic function during puberty. Horm Behav. 

2010;58(1):122-37. 

Quinn JJ, Hitchcott PK, Umeda EA, Arnold AP, Taylor JR. Sex chromosome complement 

regulates habit formation. Nat Neurosci. 2007 Nov;10(11):1398-400. 

77
Effect of the Menstrual Cycle on Drug Abuse Treatment 

Findings from human and animal studies show that the menstrual cycle (estrus cycle in animals) influences the reinforcing and positive subjective effects of abused drugs, and that 

estradiol facilitates these effects while progesterone opposes them. This line of research is 

providing evidence that synchronizing drug addiction treatment (e.g., nicotine cessation) 

with the menstrual cycle may improve treatment outcomes, and that progesterone or 

progesterone-like compounds could prove useful in treating drug addiction. (NIDA) 

References: 

Evans SM, Foltin RW. Does the response to cocaine differ as a function of sex or hormonal 

status in human and non-human primates? Horm Behav. 2010;58(1):13-21. 

Carroll ME, Anker JJ. Sex differences and ovarian hormones in animal models of drug 

dependence. Horm Behav. 2010;58(1):44-56. 

Mello NK. Hormones, nicotine, and cocaine: clinical studies. Horm Behav. 2010;58:57-71. 

Alcohol Use and Abuse 

Brain Development and Maternal Alcohol Use 

Normal development of the brain requires ordered migration of immature neurons, a process 

that is disrupted by neonatal exposure to alcohol. In an animal model of fetal alcohol syndrome, 

scientists found that alcohol alters neuronal migration through its effects on the levels of specific signaling molecules in the cell (calcium ions and cyclic nucleotides). Reversing the effects 

of alcohol on these signaling processes also reversed its effects on neuronal migration, suggesting potential avenues for preventing alcohol’s harmful effects in early development. (NIAAA) 

Reference: 

Kumada T, Lakshmana MK, Komuro H. Reversal of neuronal migration in a mouse model of 

fetal alcohol syndrome by controlling second-messenger signalings. J Neurosci. 2006 Jan 

18;26(3):742-56. 

Fetal Alcohol Exposure and Future Alcohol Use 

Studies conducted in humans have shown that fetal alcohol exposure may increase susceptibility to adolescent alcohol abuse. A study investigated the mechanisms by which fetal alcohol 

exposure might influence the desire for alcohol later in life. Researchers gave alcohol to pregnant rats, and then tested their pups for taste and olfactory responses to alcohol and quinine. 

Rat pups that were exposed to alcohol before birth had a greater preference for the taste of 

both alcohol and quinine hydrochloride (bitter) than did animals that had not been exposed to 

alcohol before birth. A significant proportion of the increased alcohol taste preference could 

be attributed directly to the weakened aversion to alcohol’s quinine-like taste quality. Fetal 

alcohol exposure also increased the pups’ alcohol intake and the behavioral response to alcohol odor. Thus, fetal alcohol exposure can affect the developing sensory (smell and taste) 

systems of the brain in a way that enhances alcohol preference later in life. (NIAAA) 

78
Reference: 

Youngentob SL, Glendinning JI. Fetal ethanol exposure increases ethanol intake by making it 

smell and taste better. Proc Natl Acad Sci USA. 2009 Mar 31;106(13):5359-64. 

Excessive Alcohol Consumption during Puberty May Affect Development of 

the HPA 

Maternal alcohol consumption during critical periods of fetal brain development leads to 

devastating long-term consequences on adult reproductive physiology, cognitive function, 

and social behaviors. However, very little is known about the long-term consequences of 

alcohol consumption during puberty, which is perhaps an equally dynamic and critical period 

of brain development. An important neurological system that undergoes extensive plasticity 

during pubertal development is the hypothalamo-pituitary-adrenal (HPA) axis. A study contrasted the HPA axis effects of binge alcohol exposure in rats during the peripubertal period to 

that of acute exposure. The effects of alcohol on the HPA axis are sex-specific and are dependent on repeated high-dose exposures. This contribution provides the first characterization 

of the impact of binge alcohol exposure during adolescence on the HPA axis. Binge exposure 

produces a lasting effect on HPA reactivity and an effect different from that induced by acute 

alcohol exposure. (NIAAA) 

Reference: 

Przybycien-Szymanska MM, Rao YS, Pak, TR. Binge-pattern alcohol exposure during puberty 

induces sexually dimorphic changes in genes regulating the HPA axis. Am J Physiol Endocrinol 

Metab. 2010 Feb;298(2):320-8. 

Treatment with Phosphodiesterase Inhibitors May Counteract the 

Effects of FASD 

Fetal alcohol spectrum disorders (FASD) are the leading cause of mental retardation in the 

Western world and children with FASD present altered somatosensory, auditory, and visual 

processing. There is growing evidence that some of these sensory processing problems may 

be related to altered cortical maps caused by impaired developmental neuronal plasticity. Using the ferret visual cortex as a model, investigators previously established that fetal 

alcohol impairs neuronal plasticity, which could account for altered sensory processing associated with FASD. This impaired plasticity in the visual cortex is accompanied by sustained 

reductions in the levels of active, phosphorylated CREB (pCREB), an established mediator 

of plasticity. Furthermore, subsequent treatment with a phosphodiesterase (PDE) inhibitor, 

vinpocetine, corrected pCREB levels and, more importantly, dramatically restored neuronal plasticity. These findings suggest that PDE inhibition might be an effective therapeutic 

strategy for correcting sensory and possibly other neuronal functional deficits in individuals 

affected by FASD. (NIAAA) 

Reference: 

Krahe TE, Wang W, Medina AE. Phosphodiesterase inhibition increases CREB phosphorylation 

and restores orientation selectivity in a model of fetal alcohol spectrum disorders. PLoS One. 

2009 Aug 14;4(8):e6643. 

79
Gender Differences in Age of Onset of Drinking Accounts for Gender 

Differences in Lifetime Prevalence of Alcohol Dependence 

Researchers evaluated secular trends in ages at onset of drinking to determine whether 

they can account for secular changes in alcohol dependence, using data from the combined 

National Longitudinal Alcohol Epidemiologic Survey (NLAES) and National Epidemiologic 

Survey on Alcohol and Related Conditions (NESARC), two nationally representative surveys 

that were conducted 10 years apart. Both men and women born between 1944 and 1963 had 

earlier ages of onset of drinking (AOD) than did the earliest birth cohort analyzed (1934-

1943). However, the net decrease in AOD was twice as large for women (3.2 years) than for 

men (1.6 years). After adjusting for AOD, differences in lifetime prevalence between different birth cohorts of women were rendered nonsignificant, indicating that AOD accounts for a 

substantial portion of change in the lifetime prevalence of alcohol dependence. These results 

suggest that a decrease in AOD accounts for much of the increase in lifetime alcohol dependence among women. AOD is likely to be an indicator of dynamic, and therefore modifiable, 

risk behaviors impacting risk for alcohol dependence. (NIAAA) 

Reference: 

Grucza RA, Norberg K, Bucholz KK, Bierut LJ. Correspondence between secular changes in 

alcohol dependence and age of drinking onset among women in the United States. Alcohol 

Clin Exp Res. 2008 Aug;32(8):1493-501. 

Employment and Abstinence Outcomes for Women May Depend on 

Treatment Type 

Among substance-dependent women receiving Temporary Assistance for Needy Families 

(TANF), investigators compared abstinence rates and employment outcomes for those who 

entered intensive case management (ICM) and those assigned to a screen-and-refer program 

(i.e., usual care). Abstinence rates were higher for the ICM group than for the usual care group 

through 24 months of follow-up. Additionally, women in the ICM group were more likely to be 

employed full time than women in the usual care group. Thus, ICM appears to be a promising intervention for managing substance dependence among women receiving TANF and for 

improving employment rates among this vulnerable population. (NIAAA) 

Reference: 

Morgenstern J, Neighbors CJ Kuerbis A, Riordan A, Blanchard KA, McVeigh KH, Morgan TJ, 

McCrady B. Improving 24-month abstinence and employment outcomes for substancedependent women receiving temporary assistance for needy families with intensive case 

management. Am J Public Health. 2009 Feb;99(2):328-33. 

80
The Correlation between Sexual Abuse, Alcohol Use, and Risky Behavior 

in Women 

Correlational studies have established that sexually abused (SA) women, particularly women 

abused in childhood (CSA), are at higher risk of contracting HIV/sexually transmitted infections 

(STIs) than are non-SA women. An experimental evaluation of potential differences in women’s likelihood of sexual risk undertaken in a laboratory setting based on alcohol intoxication 

and sexual abuse history demonstrated that intoxicated CSA women reported significantly 

more likelihood of unprotected oral sex and less likelihood of condom use relative to intoxicated non-sexually abused women and those sexually abused in adulthood and sober CSA 

women. CSA women’s increased risk of STIs may be driven by lack of condom use and behavioral changes while intoxicated. These findings provide preliminary insight into situational 

influences affecting CSA women’s increased STI risk. (NIAAA) 

Reference: 

Schacht RL, George WH, Davis KC, Heiman JR, Norris J, Stoner SA, Kajumulo KF. Sexual 

abuse history, alcohol intoxication, and women’s sexual risk behavior. Arch Sex Behav. 2010 

Aug;39(4):898-906. 

Modeling Can Help Shape and Test Interventions to Curb Drinking on 

College Campuses 

The misuse and abuse of alcohol among college students remain persistent problems. Using a 

systems approach to understand the dynamics of student drinking behavior and thus forecast 

the impact of campus policy to address the problem represents a novel approach. Toward this 

end, researchers developed a deterministic, compartmental model of college drinking incorporating three processes: (1) individual factors, (2) social interactions, and (3) social norms. 

The model quantified these processes in terms of the movement of students between drinking compartments characterized by five styles of college drinking: abstainers, light drinkers, 

moderate drinkers, problem drinkers, and heavy episodic drinkers. Predictions from the model 

were first compared with actual campus-level data and then used to predict the effects of 

several simulated interventions to address heavy episodic drinking. The model was found to 

adequately predict the actual drinking patterns of students from a variety of campuses surveyed in the Social Norms Marketing Research Project study. The model predicted the impact 

on drinking patterns of several simulated interventions to address heavy episodic drinking on 

various types of campuses. These findings provide a novel method for testing the likely effectiveness of preventive policy interventions prior to campuses having to expend resources on a 

trial-and-error basis. Thus, employment of such methods has great potential to contribute to 

future research on prevention effectiveness. (NIAAA) 

Reference: 

Scribner R, Ackleh AS, Fitzpatrick BG, Jacquez G, Thibodeaux JJ, Rommel R, Simonsen N. 

A systems approach to college drinking: development of a deterministic model for testing 

alcohol control policies. J Stud Alcohol Drugs. 2009;70(5):805-21. 

81
Adolescent Alcohol-Related Sexual Aggression May Predict Adult Alcoholism 

and Aggression 

A Web-based survey administered to 1,220 7th- to 12th-grade students from a middle school 

and high school in southeastern Michigan demonstrated that youth reporting alcohol-related 

sexual assault aggression represent a high-risk group for both sexual perpetration and alcoholism during adulthood. The fact that distinctions can be identified in youth suggests that 

targeted interventions during middle school and high school may be feasible. (NIAAA) 

Reference: 

Young AM, King L, Abbey A, Boyd CJ. Adolescent peer-on-peer sexual aggression: characteristics of aggressors of alcohol and non-alcohol-related assault. J Stud Alcohol Drugs. 2009 

Sep;70(5):700-3. 

Correlation between Heavy Alcohol Use and Educational Attainment Varies 

by Gender 

Although teenage alcohol use is well correlated with school failure and reduced educational 

attainment, it is unclear whether this relationship is causal or spurious. Using data from the 

National Child Development Study, an ongoing longitudinal birth cohort study of British youth 

born in 1958 (N = 9,107), the authors of this study investigated the long-term impact of heavy 

alcohol use at age 16 years on educational qualifications in adulthood. Drawing on a lifespan 

developmental contextual approach, they found that heavy teenage alcohol use and disadvantaged social origins combined to diminish male educational attainment. In contrast, heavy 

alcohol use had little effect on female educational attainment. Future long-term longitudinal 

research is needed to replicate these findings for more recent birth cohorts and for populations outside of Britain. (NIAAA) 

Reference: 

Staff J, Patrick ME, Loken E, Maggs JL. Teenage alcohol use and educational attainment. 

J Stud Alcohol Drugs. 2008 Nov;69(6):848-58. 

MENTAL HEALTH 

Sex Differences in Mental Health 

Women Are More Likely Than Men to Develop Some Mental Health Disorders 

Epidemiological research demonstrates that women are more likely than men to develop 

certain mental health disorders, such as depression, eating disorders, panic disorder, and 

post-traumatic stress disorder (PTSD). Men are more likely to develop attention deficit/ 

hyperactivity disorder, impulse-control disorders, and alcohol dependence and drug dependence. Investigators, through the ORWH Building Interdisciplinary Careers in Women’s Health 

(BIRCWH) program, are also studying fetal antecedents to depression and schizophrenia in 

men and women. These findings offer insight into differences in brain development between 

men and women and possible crucial periods of development in men and women, which may 

lead to more accurately targeted prevention and treatment efforts. (NIMH) 

82
References: 

Goldstein JM, Seidman LJ, O’Brien LM, Horton NJ, Kennedy DN, Makris N, Caviness VS Jr, Faraone SV, Tsuang MT. Impact of normal sexual dimorphisms on sex differences in structural brain 

abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch Gen Psychiatry. 

2002 Feb;59(2):154-64. 

Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and 

age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005 Jun;62(6):593-602. 

Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the 

National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 

1993 Oct-Nov;29(2-3):85-96. 

Walder DJ, Seidman LJ, Cullen N, Su J, Tsuang MT, Goldstein JM. Sex differences in language 

dysfunction in schizophrenia. Am J Psychiatry. 2006 Mar;163(3):470-7. 

Epigenetic and Preclinical Research on Mental Health in Women 

Ongoing studies are examining how environmental factors like diet, stress, and others can 

alter gene function. These studies are helping to identify factors that may also influence men’s 

and women’s different risks for developing depression and other disorders, and are revealing 

potential new molecular targets for treating mental health disorders in women. (NIMH) 

References: 

Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, 

Meaney MJ. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7(8):847-54. 

McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood 

abuse. Nat Neurosci. 2009;12(3):342-8. 

Post-Traumatic Stress Disorder 

Women and Post-Traumatic Stress Disorder 

Post-traumatic stress disorder is an anxiety disorder that can develop after exposure to a terrifying event or ordeal in which grave physical harm occurred or was threatened. Traumatic 

events that may trigger PTSD include violent personal assaults, natural or human-caused 

disasters, accidents, or military combat. Women experience PTSD at twice the rate of men. 

In 2008, NIMH facilitated the launch of a major study of the genetics of PTSD in women. This 

project is embedded within the Nurses’ Health Study II (NHS), a large prospective epidemiologic cohort of women. Identification of genes responsible for PTSD would represent a major 

advance in understanding the pathophysiology of the disorder. Such understanding could lead 

to the development of new PTSD treatments and preventive interventions as well. It would 

also help identify those at high risk for developing PTSD, making it possible to provide early 

intervention to those most in need. (NIMH) 

83
References: 

Cornelis MC, Nugent NR, Amstadter AB, Koenen KC. Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Curr Psychiatry Rep. 

2010 Aug;12(4):313-26. 

Koenen KC, De Vivo I, Rich-Edwards J, Smoller JW, Wright RJ, Purcell SM. Protocol for investigating genetic determinants of posttraumatic stress disorder in women from the Nurses’ 

Health Study II. BMC Psychiatry. 2009 May; 9:29. 

Koenen KC, Nugent N, et al. Gene-environment interaction in posttraumatic stress disorder: 

review, strategy and new directions for future research. J Trauma Stress. 2008 Feb;21(1):49-57. 

Koenen KC, Widom CS. A prospective study of sex differences in the lifetime risk of posttraumatic stress disorder among abused and neglected children grown up. J Trauma Stress. 2009 

Dec;22(6):566-74. 

Kubzansky LD, Koenen KC, Jones C, Eaton WW. A prospective study of posttraumatic stress disorder symptoms and coronary heart disease in women. Health Psychol. 2009 Jan; 28(1):125-30. 

Maikovich AK, Koenen KC, Jafee SR. Posttraumatic stress symptoms and trajectories in child 

sexual abuse victims: an analysis of sex differences using the National Survey of Child and 

Adolescent Well-being. J Abnorm Child Psychol. 2009 Jul;37(5):727-37. 

Depression 

Advances in Diagnosis and Treatment of Postpartum Depression 

Research demonstrates that postpartum depression is a serious and debilitating disorder that 

affects up to 15 percent of new mothers. Women with depression who stop antidepressant 

treatment during pregnancy are at higher risk for relapse, and their risk of postpartum depression is significantly elevated as well. Several forms of treatment, including cognitive behavioral 

therapy (CBT), interpersonal psychotherapy (IPT), and medication treatment are effective in 

treating this disorder. Research continues into prevention efforts and improved service delivery of treatments based on individual needs. (NIMH) 

References: 

Cox JL, Murray D, Chapman G. A controlled study of the onset, duration and prevalence of 

postnatal depression. Br J Psychiatry. 1993 Jul;163:27-31. 

Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during 

pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 

1;295(5):499-507. Erratum in: JAMA. 2006 Jul 12;296(2):170. 

Dimidjian S, Goodman S. Nonpharmacologic intervention and prevention strategies for depression during pregnancy and the postpartum. Clin Obstet Gynecol. 2009 Sep;52(3):498-515. 

Gaynes BN, Gavin N, Meltzer-Brody S, Lohr KN, Swinson T, Gartlehner G, Brody S, Miller WC. 

Perinatal depression: prevalence, screening accuracy, and screening outcomes. Evidence 

84
Report/Technology Assessment no. 119. Prepared by the RTI-University of North Carolina 

Evidence-based Practice Center, under contract no. 290-02-0016. AHRQ Publication No. 05- 

E006-2. Rockville, MD: Agency for Healthcare Research and Quality; 2005 Feb. 

O’Hara MW, Stuart S, Gorman LL, Wenzel A. Efficacy of interpersonal psychotherapy for postpartum depression. Arch Gen Psychiatry 2000;57(11):1039-45. 

Wisner KL, Sit DK, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Jones-Ivy S, 

Bodnar LM, Singer LT. Major depression and antidepressant treatment: impact on pregnancy 

and neonatal outcomes. Am J Psychiatry. 2009 May;166(5):557-66. 

Sex Differences in Nerve Growth Factors May Impact Depression 

Research has found sex-related differences in the role of the nerve growth factor BDNF (brainderived neurotrophic factor), which is believed to play a role in depression and in the response 

to antidepressants. Acute and chronic stress decreases levels of BDNF. In studies using mice 

in which the BDNF gene is turned off, females showed decreases in anxiety-like behaviors relative to controls, but males did not. These results support a possible specific role of BDNF in 

anxiety- and depression-related behaviors in females. They further demonstrate the importance of examining both sexes for potential genetic effects on mood behaviors. (NIMH) 

Reference: 

Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S, Parada LF, Nestler EJ. 

Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry. 2007 Jan 15;61(2):187-97. 

Depression Is Often Comorbid with Other Mental Illnesses 

Depression often coexists with eating disorders such as anorexia nervosa, bulimia nervosa, and 

others, especially among women. Anxiety disorders, such as post-traumatic stress disorder, 

obsessive-compulsive disorder, panic disorder, social phobia, and generalized anxiety disorder, also sometimes accompany depression, especially among women. Women suffering from 

post-traumatic stress disorder are especially prone to also having depression. (NIMH) 

References: 

Devane CL, Chiao E, Franklin M, Kruep EJ. Anxiety disorders in the 21st century: status, challenges, opportunities, and comorbidity with depression. Am J Manag Care. 2005 Oct;11(Suppl. 

12): S344-53. 

Kessler RC, Barker PR, Colpe LJ, Epstein JF, Gfroerer JC, Hiripi E, Howes MJ, Normand SL, 

Manderscheid RW, Walters EE, Zaslavsky AM. Screening for serious mental illness in the general population. Arch Gen Psychiatry. 2003 Feb; 60(2):184-9. 

Regier DA, Rae DS, Narrow WE, Kaelber CT, Schatzberg AF. Prevalence of anxiety disorders and 

their comorbidity with mood and addictive disorders. Br J Psychiatry Suppl. 1998;(34):24-8. 

85
Depression Is Often Comorbid with a Range of Medical Illnesses 

Depression also often coexists with medical illnesses such as heart disease, stroke, cancer, 

HIV/AIDS, diabetes, Parkinson disease, thyroid problems, and multiple sclerosis, and may 

make symptoms of the illness worse. A study conducted by the NIMH and NIDDK Intramural Research Programs showed that premenopausal women with even mild depression have 

less bone mass than their nondepressed peers. The level of bone loss is at least as high as 

that associated with recognized risk factors for osteoporosis, including smoking, low calcium 

intake, and lack of physical activity. Studies have also shown that both women and men who 

have depression plus a serious medical illness tend to have more severe symptoms of both illnesses. They also have more difficulty adapting to their medical conditions and more medical 

costs than those who do not have coexisting depression. Research has shown that treating the 

depression along with the coexisting illness will help ease both conditions. (NIMH)
�

References:
�

Cassano P, Fava M. Depression and public health, an overview. J Psychosom Res. 2002 

Oct;53(4):849-57.
�

Eskandari F, et al. Low bone mass in premenopausal women with depression. Arch Intern Med. 

2007 Nov 26;167(21):2329-36.
�

Katon W, Ciechanowski P. Impact of major depression on chronic medical illness. J Psychosom 

Res. 2002 Oct;53(4):859-63.
�

Use of Medications to Treat Depression Has Increased in Women 

Over the past 20 years, progress has been made in standardizing effective psychotherapy 

interventions such as cognitive behavioral therapy and interpersonal therapy (IPT), and in 

trials of medication treatment. The class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) has come into widespread use and improves the quality of life for many 

women. Researchers have also learned that women are much more likely to seek treatment 

than men. (NIMH) 

Reference: 

Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental 

health services in the United States: results from the National Comorbidity Survey Replication. 

Arch Gen Psychiatry. 2005 Jun;62(6):629-40. 

Neuroimaging and the Menstrual Cycle 

Neuroimaging research has revealed a unique reward-related pattern of brain activation during different phases of the menstrual cycle. These data demonstrate that sex hormones affect 

the function of the reward system. These hormones regulate areas of the brain involved with 

mood and emotion and are implicated in depression. (NIMH) 

Reference: 

Dreher JC, Schmidt PJ, Kohn P, Furman D, Rubinow D, Berman KF. Menstrual cycle phase modulates reward-related neural function in women. Proc Natl Acad Sci USA. 2007;104(7):2465-70. 

86
Estrogen and Depression 

Studies have demonstrated the antidepressant role of estradiol (estrogen) therapy during perimenopause. Other researchers have shown the effectiveness of antidepressant medications, 

given premenstrually, in reducing symptoms. The NIMH Intramural Research Program also has 

shown that lower levels of estradiol can precede depression but only in women with a past 

history of perimenopausal depression. Other studies have found that mood changes may be 

associated with low hormonal levels in women who have a past history of major depression, 

but not in those without such a history. (NIMH) 

References: 

Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157(6):924-30. 

Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, Rubinow DR. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gyn. 

2000;183(2):414-20. 

Depression and Premature Ovarian Insufficiency 

Lifetime prevalence of depression in women with premature ovarian insufficiency is significantly greater than that in the general population. First episodes of major depression 

preceded a POI diagnosis in more than 70 percent of women studied. A better understanding 

of this association could identify physiological and genetic processes that underlie depression 

and POI, as well as the association between depression and the menopause transition in the 

typical menopause experience. (NIMH) 

Reference: 

Schmidt PJ, Cardoso GM, Ross JL, Haq N, Rubinow DR, Bondy CA. Shyness, social anxiety, and impaired self-esteem in Turner Syndrome and premature ovarian failure. JAMA. 

2006;295(12):1374-6. 

Onset of Depression during Perimenopause 

Two large NIMH- and NIA-funded studies in the past decade have confirmed that women are significantly more likely to experience a first-time major depressive episode in the perimenopausal 

period than at other life stages. In a study that was part of the Harvard Study of Moods and 

Cycles, researchers showed that premenopausal women with no lifetime history of major depression who then entered the perimenopause were twice as likely to develop significant depressive 

symptoms compared with women who remained premenopausal during the study. The researchers also found that high rates of depression were four times more likely to occur during a 

women’s menopausal transition compared with when she was in premenopause. (NIMH) 

References: 

Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during 

the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006 

Apr;63(4):385-90. 

87
Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006 

Apr;63(4):375-82. 

Reproductive Hormones and Mood Disorders 

The reproductive endocrine system may play a major role in mood disorders among women. 

NIMH’s Intramural Behavioral Endocrinology Program is working to better understand the neurobiology of these conditions. Researchers have found that changes in reproductive hormones 

can cause mood disorders. Age, ovarian hormones, and the extent to which hormone level 

varies across the menstrual cycle can influence whether a woman develops a mood disorder. 

The same hormonal changes could cause different effects on mood and behavior at different 

stages of the same woman’s life. (NIMH) 

References: 

Daly RC, Danaceau MA, Rubinow DR, Schmidt PJ. Concordant restoration of ovarian function 

and mood in perimenopausal depression. Am. J. Psychiatry. 2003;160(10):1842-6. 

Morrison JH, Brinton RD, Schmidt PJ, Gore AC. Estrogen, menopause, and the aging brain: how 

basic neuroscience can inform hormone therapy in women. J. Neurosci. 2006;26(41):10332-48. 

Schmidt PJ, Daly RC, Bloch M, Smith MJ, Danaceau MA, St Clair LS, Murphy JH, Haq N, 

Rubinow DR. Dehydroepiandrosterone monotherapy in midlife-onset major and minor 

depression. Arch. Gen. Psychiatry. 2005;62(2):154-62. 

Schmidt PJ. Mood, depression, and reproductive hormones in the menopause transition. 

Am. J. Med. 2005;118(12B):54S-58S. 

Hormonal Transitions and Depression 

The NIMH Intramural Research Program’s scientists and other researchers have been investigating why women are more prone to depression throughout life, and what prevention and 

treatment efforts can be brought to bear upon this high burden. Scientists are studying why 

and how some women are more sensitive to hormonal changes, which may help explain why 

depression rates among women tend to rise during puberty, around pregnancy, and before 

and during menopause. It also may lead to a better understanding of premenstrual dysphoric 

disorder, a very severe form of premenstrual syndrome. (NIMH) 

References: 

Bloch M, Rubinow DR, Berlin K, Kevala KR, Kim HY, Schmidt PJ. Monoamines and neurosteroids in sexual function during induced hypogonadism in healthy men. Arch Gen Psychiatry. 

2006;63(4):450-6. 

Huo L, Straub RE, Roca C, Schmidt PJ, Shi K, Vakkalanka R, Weinberger DR, Rubinow DR. Risk 

for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen 

receptor alpha gene. Biol Psychiatry. 2007;62(8):925-33. 

Richards M, Rubinow DR, Daly RC, Schmidt PJ. Premenstrual symptoms and perimenopausal 

depression. Am J Psychiatry. 2006;163(1):133-7. 

88
Roca CA, Schmidt PJ, Altemus M, Deuster P, Danaceau MA, Putnam K, Rubinow DR. Differential 

menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual 

syndrome and controls. J Clin Endocrinol Metab. 2003;88(7):3057-63. 

Roca CA, Schmidt PJ, Deuster PA, Danaceau MA, Altemus M, Putnam K, Chrousos GP, Nieman 

LK, Rubinow DR. Sex-related differences in stimulated hypothalamic-pituitary-adrenal axis 

during induced gonadal suppression. J Clin Endocrinol Metab. 2005 Jul;90(7):4224-31. Erratum in: J Clin Endocrinol Metab. 2005 Sep;90(9):5522 

Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry. 2004;161(12):2238-44. 

Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects 

of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 

1998;338(4):209-16. 

Yonkers KA, Holthausen GA, Poschman K, Howell HB. Symptom-onset treatment for women 

with premenstrual dysphoric disorder. J Clin Psychopharmacol. 2006 Apr;26(2):198-202. 

89
Immunity, Autoimmunity, and Infectious Diseases
�

Microorganisms and Early Immune Responses Involved in the Development 

of Inflammation and Autoimmune Disease 

NIAID-funded investigators showed that mice with a defect in a specific gene called SHP1, 

which is involved in dampening immune responses, developed chronic inflammation in their 

feet, lungs and salivary glands. In addition, the mice produced self-reactive antibodies, a sign 

of autoimmune disease. The observed inflammatory and autoimmune response in the SHP-1 

mutant mice did not occur when the mice were kept in a germ-free environment. Inflammation was also prevented when specific signaling genes of the early, or innate, immune system 

were deleted in the SHP-1 mutant mice. Studies in this mouse model define a mechanism for 

the development of inflammation and autoimmunity: a dependence on both the presence of 

microbial pathogens and signaling through innate immune pathways. (NIAID) 

Reference: 

Croker BA, Lawson BR, et al. Inflammation and autoimmunity caused by SHP1 mutation depend 

on IL-1, MyD88, and a microbial trigger. Proc Natl Acad Sci USA. 2008:105(39):15028-33. 

Gender Differences in Response to Stress 

Researchers in one study found that 30 minutes after experiencing a stressful event, production of pro-inflammatory cytokines were elevated in both men and women. However, from 

before to immediately post-stress, men demonstrated a significant drop in cytokine production compared with women. Further, postmenopausal women demonstrated greater 

subsequent increases in the production of certain cytokines compared with men. These data 

bolster existing evidence that stress causes the immune system in postmenopausal women 

to produce larger inflammatory responses than in either premenopausal women or men. The 

results also demonstrate gender differences in stress-related cytokine activity, and suggest 

a possible reason for an observed increased susceptibility of postmenopausal women for 

developing inflammatory disease. (NINR) 

Reference: 

Prather AA, Carroll JE, Fury JM, McDade KK, Ross D, Marsland AL. Gender differences in 

stimulated cytokine production following acute psychological stress. Brain Behav Immun. 

2009;23(5):622-8. 

Candidate GBS Vaccine Shown To Be Safe 

A group B Streptococcus (GBS) serotype III polysaccharide tetanus toxoid vaccine was found 

to be safe, elicit a strong immune response, and significantly reduce bacterial colonization (36 

percent in the vagina and 43 percent in the rectum) in 650 women studied. This response indicates that such a candidate vaccine may prevent invasive infections by decreasing colonization 

at mucosal sites. (NIAID) 

90
Reference: 

Hillier, et al. Women receiving group B Streptococcus serotype III tetanus toxoid (GBS III-TT) 

vaccine have reduced vaginal and rectal acquisition of GBS type III. Presented at the 47th 

Annual Meeting of the Infectious Diseases Society of America; 2009 Oct 30; Philadelphia, PA. 

Newborn Screening for CMV 

A study funded by NIDCD has found that the traditional “heel stick” test is not an effective 

screening tool for congenital cytomegalovirus (CMV) infection, a leading cause of hearing 

loss in children. Researchers compared the effectiveness of a common molecular diagnostic 

technology using dried blood samples to the standard method for detecting CMV in newborns, which is labor-intensive and not conducive to a widespread screening program. The 

researchers are now assessing whether analysis of saliva samples using the same diagnostic technology can do a better job than dried blood spots when compared with the standard 

method. (NIDCD) 

Reference: 

Boppana SB, et al. Dried blood spot real-time polymerase chain reaction assays to screen 

newborns for congenital cytomegalovirus infection. JAMA. 2010 Apr 14;303(14):1375-82. 

HEPATITIS 

Development of a Hepatitis E Vaccine with Potential to Reduce 

Maternal Mortality 

Infection by the food- and waterborne pathogen hepatitis E virus (HEV) can cause 10 to 

25 percent fatality rates among HEV-infected pregnant women, and can adversely affect 

pregnancy outcomes among survivors. An HEV vaccine developed by NIAID scientists, in collaboration with GlaxoSmithKline (GSK), has been proven safe and effective in field trials 

supported by the U.S. Army Medical Research and Materiel Command, NIAID, and GSK. Distribution of this vaccine in endemic areas could have an important effect on public health, 

especially the health of pregnant women. (NIAID) 

References: 

Robinson RA, Burgess WH, Emerson SU, Leibowitz RS, Sosnovtseva SA, Tsarev S, Purcell RH. 

Structural characterization of recombinant hepatitis E virus ORF2 proteins in baculovirusinfected insect cells. Protein Expr Purif. 1998;12(1):75-84. 

Shrestha MP, Scott RM, Joshi DM, Mammen MP Jr, Thapa GB, Thapa N, Myint KS, Fourneau M, 

Kuschner RA, Shrestha SK, David MP, Seriwatana J, Vaughn DW, Safary A, Endy TP, Innis BL. 

Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med. 2007;356(9):895-903. 

Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, Purcell RH. Recombinant vaccine against hepatitis E: dose response and protection against heterologous 

challenge. Vaccine. 1997;15(17-18):1834-8. 

91
H1N1 (SWINE) FLU 

H1N1 Vaccine Trials in Pregnant Women 

NIAID, through its Vaccine and Treatment Evaluation Units, has recently conducted several 

studies evaluating influenza vaccines in pregnant women. Because pregnant women were 

disproportionately affected by the 2009 H1N1 pandemic, NIAID launched studies to assess 

whether higher vaccine dosages or more than one dose should be recommended for this population. Early results—indicating that a single 15 mg dose produces a robust immune response 

in this population—helped shape treatment guidelines. Studies looking at HIV-infected pregnant women are also under way. (NIAID) 

LUPUS 

Gene Expression in Lupus Patients 

Using a new global gene expression analysis approach, researchers discovered a gene expression pattern of interferon-regulated genes that correlated with disease activity in systemic 

lupus erythematosus patients. This molecular pattern is clinically important, as it may be a 

useful biomarker to predict the therapeutic efficacy of experimental drugs for lupus. This basic 

research finding also led to several studies in which clinicians are testing new treatments for 

lupus that block interferon alpha. (NIAID) 

Reference: 

Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197(6):711-23. 

Prevalence and Severity of Lupus in Various Populations of Women 

Systemic lupus erythematosus, or lupus, is a chronic inflammatory disease that can affect 

many organs of the body, including the skin, joints, heart, lungs, kidneys, and brain. Substantial research accomplishments have been made to characterize this complex disease, which 

has diverse effects across the patient population, in efforts to treat individual patients. The 

Lupus in Minority Populations: Nature vs. Nurture (LUMINA) study revealed that female Hispanic and African-American lupus patients tend to develop the disease at a younger age than 

their Caucasian counterparts and experience greater disease activity and more severe manifestations of lupus. (NIAMS) 

References: 

Alarcón GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, Bastian HM, McGwin G Jr, Bartolucci AA, Roseman JM, Reveille JD. Systemic lupus erythematosus in three ethnic groups: III. 

A comparison of characteristics early in the natural history of the LUMINA cohort. Lupus in 

Minority populations: Nature vs. Nurture. Lupus. 1999;8(3):197-209. 

Bastian HM, et al. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for 

lupus nephritis after diagnosis. Lupus. 2002;11(3):152-60. 

92
Advances in Detection and Treatment of Lupus 

The Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) clinical trial 

addressed concerns over the impact of estrogen-based oral contraceptives on disease activity and has shown they can be used safely without directly inducing lupus flares. Methods 

to analyze patients’ blood samples are being developed to group variations in gene expression according to the different disease-causing molecular pathways in individual patients. This 

system may be used to predict flares of lupus activity in the future and guide personalized 

treatment. (NIAMS) 

References: 

Petri M, et al. Combined oral contraceptives in women with systemic lupus erythematosus. 

N Eng J Med. 2005 Dec 15,353(24):2550-8. 

Chaussabel D, Quinn C, Shen J, Patel P, Glaser C, Baldwin N, Stichweh D, Blankenship D, Li L, 

Munagala I, Bennett L, Allantaz F, Mejias A, Ardura M, Kaizer E, Monnet L, Allman W, Randall H, 

Johnson D, Lanier A, Punaro M, Wittkowski KM, White P, Fay J, Klintmalm G, Ramilo O, Palucka 

AK, Banchereau J, Pascual V. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity. 2008 Jul 18;29(1):150-64. 

Lupus and Pregnancy 

Ongoing studies from the Research Registry for Neonatal Lupus and the multicenter study 

called Predictors of Pregnancy Outcome, Biomarkers in Antiphospholipid Syndrome and 

Systemic Lupus Erythematosus (PROMISSE) are investigating the role of autoantibodies 

and other serum molecules from pregnant lupus patients in increasing the risk of neonatal 

lupus syndrome and associated cardiovascular complications. (NIAMS) 

References: 

Buyon JP, Hiebert R, Copel J, Craft J, Friedman D, Katholi M, Lee LA, Provost TT, Reichlin M, 

Rider L, Rupel A, Saleeb S, Weston WL, Skovron ML. Autoimmune-associated congenital heart 

block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998 Jun;31(7):1658-66. 

Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, Salmon JE, Buyon JP. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal 

lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis. 2010 May 6 [Epub ahead of print]. 

RHEUMATOID ARTHRITIS 

Potential Treatments for Rheumatoid Arthritis? 

In the 1990s, researchers identified molecular mechanisms of inflammation and immune 

dysfunction that could be associated with disease pathways in rheumatoid arthritis. Biologics—drugs in the form of biological molecules—that block the activity of tumor necrosis factor, 

a key molecule in inflammatory processes, have brought relief to many rheumatoid arthritis 

patients, including children, with fewer side effects than other treatments. The North American 

93
Rheumatoid Arthritis Consortium (NARAC), a multi-institutional group of researchers, is conducting ongoing studies, in collaboration with colleagues from other countries, to identify 

the genetic factors that contribute to rheumatoid arthritis susceptibility and that may affect 

responses to rheumatoid arthritis treatments. (NIAMS)
�

References:
�

Pisetsky DS. Tumor necrosis factor blockers in rheumatoid arthritis. N Eng J Med. 2000 Mar 

16;342(11):810-1.
�

Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, 

Ilowite NT, Wallace CA, Whitmore J, Finck BK. Etanercept in children with polyarticular juvenile 

rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Eng J Med. 2000 

Mar 16;342(11):763-9.
�

Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, 

Padyukov L, Kurreeman FA, Chang M, Catanese JJ, Ding B, Wong S, van der Helm-van Mil AH, 

Neale BM, Coblyn J, Cui J, Tak PP, Wolbink GJ, Crusius JB, van der Horst-Bruinsma IE, Criswell 

LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, 

Huizinga TW, Shadick NA, Weinblatt ME, de Vries N, Worthington J, Seielstad M, Toes RE, Karlson EW, Begovich AB, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. Common variants at 

CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet. 2008 Oct;40(10):1216-23.
�

Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG; BIRAC Consortium, 

Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, 

Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison 

P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov 

L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, 

Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, van der Schoot CE, van Riel 

PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP; YEAR Consortium, Wijmenga C, 

Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, 

Klareskog L, Plenge RM. Genome-wide association study meta-analysis identifies seven new 

rheumatoid arthritis risk loci. Nat Genet. 2010 Jun;42(6):508-14.
�

SCLERODERMA 

Advances in the Treatment of Scleroderma 

Scleroderma is a disease associated with excessive production of connective tissue proteins, a 

condition known as fibrosis, and tissue hardening. It affects women more often than men, and 

there is a higher prevalence in some Native American populations. The immunosuppressive 

drug cyclophosphamide may improve lung function, particularly in scleroderma patients with 

pulmonary alveolitis, and quality-of-life outcomes. The cancer drug Gleevec has been shown 

to target a molecular mediator of fibrosis, which inhibits the key process associated with 

scleroderma; Gleevec is currently being tested in clinical trials for scleroderma. (NIAMS) 

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References: 

Zhou X, Tan FK, Wang N, Xiong M, Maghidman S, Reveille JD, Milewicz DM, Chakraborty 

R, Arnett FC. Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum. 2003 

Sep;48(9):2585-92. 

Khanna D, et al. Impact of oral cyclophosphamide on health-related quality of life in patients 

with active scleroderma lung disease: results from the scleroderma lung study. Arthritis 

Rheum. 2007 May;56(5):1676-84. 

Pannu J, Asano Y, Nakerakanti S, Smith E, Jablonska S, Blaszczyk M, ten Dijke P, Trojanowska 

M. Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib 

mesylate. Arthritis Rheum. 2008 Aug;58(8):2528-37. 

SjöGREN’S SyNDROME 

Hormone Levels and Sjögren’s syndrome 

Androgen deficiency was demonstrated in a study of patients with primary Sjögren’s syndrome, 

a disease that occurs almost exclusively in women. There was no significant change in the 

levels of other hormones such as estrogen. These findings could not be linked to the use of 

oral contraceptives or menopausal hormone therapy. (NEI) 

Reference: 

Sullivan DA, Bélanger A, Cermak JM, Bérubé R, Papas AS, Sullivan RM, Yamagami H, Dana 

MR, Labrie F. Are women with Sjögren’s syndrome androgen-deficient? J Rheumatol. 2003 

Nov;30(11):2413-9. 

URINARy TRACT INFECTIONS 

The Interaction between Cranberry Juice and Antibiotics in the Treatment 

of Urinary Tract Infections 

Cranberry juice is a popular home remedy for urinary tract infections (UTIs). Because little 

is known about the potential of cranberry juice to interact with drugs, NCCAM-funded 

researchers studied the effects of cranberries on two antibiotics frequently prescribed for 

UTI: amoxicillin and cefaclor. The data showed that cranberry juice did not significantly 

affect either antibiotic’s oral absorption or renal clearance (i.e., how completely the body 

processed the drugs in the intestine and kidneys). Based on these results, the researchers 

concluded that cranberry juice cocktail, consumed in usual quantities, is unlikely to change 

the effects of these two antibiotics on UTIs. (NCCAM) 

Reference: 

Li M, Andrew MA, Wang J, Salinger DH, Vicini P, Grady RW, Phillips B, Shen DD, Anderson GD. 

Effects of cranberry juice on pharmacokinetics of beta-lactam antibiotics following oral administration. Antimicrob Agents Chemother. 2009 Jul;53(7):2725-32. 

95
THE HUMAN MICROBIOME 

The Human Microbiome Project (HMP) 

Within the body of a healthy adult, microbial cells are estimated to outnumber human cells 

by a factor of ten to one. These communities, however, remain largely unstudied, leaving 

almost entirely unknown their influence upon human development, physiology, immunity, 

and nutrition. 

The human microbiome consists of all of the DNA, or genomes, of all of the microorganisms 

present in or on the human body. Launched in 2007 as part of the NIH Roadmap for Medical 

Research, the Human Microbiome Project is a five-year effort that will produce a resource for 

researchers who are seeking to use information about the microbiome to improve human health. 

Initially, researchers plan to sequence 600 microbial genomes, completing a collection that 

will total some 1,000 microbial genomes. The remaining microbial genomes are being contributed to the collection by individual NIH Institutes and internationally funded projects. Those 

data will then be used to characterize the microbial communities present in samples taken 

from healthy human volunteers. The samples will be collected from five areas of the body: 

the digestive tract, the mouth, the skin, the nose, and the vagina. 

Following the precedents set by other large-scale genomics efforts, such as the Human 

Genome Project and the International HapMap Project, data from the Human Microbiome 

Project will be swiftly deposited in public databases. The HMP has the potential to transform 

understanding of human health and the prevention, diagnosis, and treatment of a wide range 

of conditions, particularly for women. (NHGRI) 

Reference: 

http://nihroadmap.nih.gov/hmp/ 

96
Women and HIV/AIDS 

Trans-NIH Plan for HIV/AIDS Research 

Each year, OAR develops the comprehensive Trans-NIH Plan for HIV-Related Research. 

The Plan includes chapters specifically devoted to Microbicides Research and to HIV 

Research for Women and Girls. The Plan is developed in collaboration with scientists from 

NIH, other government agencies, non-governmental organizations, and community representatives. The Plan serves as the framework for developing the annual AIDS research 

budget for each Institute or Center; determining the use of AIDS-designated dollars; and 

tracking and monitoring all NIH AIDS research expenditures. The Plan also is used to inform 

the scientific community, the public, and the HIV/AIDS-affected community about NIH 

priorities for HIV research. (OAR) 

Federal Treatment and Prevention Guidelines 

OAR provides funding and coordination for the development of U.S. Department of Health 

and Human Services Federal guidelines on the treatment of HIV infection. The guidelines 

are written, reviewed, and updated by Working Groups of HIV experts from across the 

country convened under the auspices of OAR. These working groups include HIV care 

physicians, pharmacists, researchers, and HIV treatment advocates. The guidelines on 

treatment of adults and adolescents include a section on the specific treatment of women, 

including evidence-based information. A second guidelines document addresses the treatment of pregnant women and the prevention of mother-to-child HIV transmission. These 

documents are widely considered to be the standard for HIV treatment nationally and 

internationally. The guideline documents can be accessed on the AIDSinfo Web site at http:// 

www.aidsinfo.nih.gov/Guidelines/Default.aspx?MenuItem=Guidelines. 

The Working Groups develop separate guidelines for: Treatment of Adults and Adolescents; 

Treatment of Children; Treatment of Pregnant Women and Prevention of Mother-to-Child HIV 

Transmission; and Prevention and Treatment of Opportunistic Infections. 

Through all of these activities, OAR continues to demonstrate its leadership and commitment 

to the study of HIV in women. (OAR) 

Safety of Contraception for HIV-infected Women: 

Depot Medroxyprogesterone Injectable Contraceptives (DMPA)
�

Until recently, the question of whether antiretroviral (ARV) agents affect or are affected by a 

widely used hormonal contraceptive—depot medroxyprogesterone (DMPA)—had not been 

thoroughly addressed. Safe and effective contraception is an important concern for reproductive-age women living with HIV/AIDS. Researchers conducted a study to examine the 

interactions between DMPA, a progesterone-based injectable contraceptive given every 

three months, and selected antiretroviral agents. Study results showed that DMPA remained 

at effective levels across groups for the 12 weeks after the injection. There were no pregnancies after DMPA injection. Plus, there were no significant changes in HIV RNA levels or in CD4+ 

97
cell counts after DMPA injection. The side effects of the DMPA were similar to those seen in 

women who are not infected with HIV. The study findings can reassure millions of women 

worldwide of reproductive age who are taking antiretroviral treatments that they may safely 

use DMPA as a contraceptive. (NICHD) 

Reference: 

Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, Clax PA, Muderspach L, Lertora JJ. Safety 

and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008 Feb;77(2):84-90. 

Women’s Interagency HIV Study (WIHS) 

Established in 1994, this is the largest observational study (3,500) of HIV-infected women and 

uninfected women at high risk of HIV, the majority of whom are African-American and Latina. 

With study participants at sites in six U.S. metropolitan areas, the study has yielded major discoveries about how HIV is spread, how the disease progresses, and how it can best be treated. 

WIHS has produced 440 publications dealing with women and HIV and maintains 2 million 

specimens to support ongoing and future research. The study continues to support research 

on drug resistance, coinfections, therapy use and treatment effects, genetics, metabolic abnormalities and toxicities, hormonal factors, aging, risk of cardiovascular disease, neurocognitive 

functioning, and physical impairment. (NIAID and NICHD) 

Reference: 

http://statepiaps.jhsph.edu/wihs/ 

Women’s HIV Seroincidence Study 

Initiated in 2009, this observational study will enroll 2,000 women from 10 geographically distinct high-risk areas in the United States to estimate the overall incidence of HIV-1. This study 

will provide essential information about women’s preferred recruitment and retention strategies for future intervention studies. (NIAID) 

Reference: 

http://www.hptn.org/research_studies/hptn064.asp 

Support for Research on Microbicides to Help Stop the Spread of HIV 

To further enhance research in the area of microbicides, OAR reorganized its scientific staff 

to add a new division specifically dedicated to planning, coordinating, budgeting, and facilitating trans-NIH microbicide research and other issues relevant to research on women and 

girls. This has resulted in elevating the scientific priority and funding for this important area 

within the overall HIV prevention research agenda. OAR has utilized its unique budgetary 

authority to ensure that funding for microbicide research continues to increase, even during 

these times of budgetary constraints. OAR also revised its AIDS Research Information System 

(ARIS) to code, track, and monitor all trans-NIH investments in and expenditures on microbicide research. (OAR) 

98
Microbicide Innovation Program (MIP) 

Topical microbicides are agents which when applied vaginally, rectally, and/or on the penis 

can result in inhibition of the transmission of HIV and/or other sexually transmitted infections 

that may be cofactors in HIV transmission and acquisition. A safe, effective, acceptable topical 

microbicide that prevents the sexual transmission of HIV could play a major role in worldwide 

reduction of the more than 7,000 new HIV infections per day, potentially saving millions of 

lives. The MIP supports the advancement of novel scientific ideas, models, tools, agents, targets, and technologies with the potential to advance microbicide science. (NIAID) 

Reference: 

http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-10-011.html 

Microbicide and Pre-exposure Prophylaxis Trials 

Research is under way to develop and test new chemical and biological compounds that 

women can apply before intercourse to protect themselves against HIV and other sexually 

transmitted infections. The VOICE study (Vaginal and Oral Interventions to Control the Epidemic) will enroll approximately 5,000 women in Africa to provide additional safety and 

effectiveness data for a tenofovir-based vaginal gel as an HIV prevention method. The study 

also will offer some insight as to the gel’s acceptability as a product used once a day, rather 

than one that is used before and after sexual intercourse. The study also is examining oral 

antiretroviral tablets (tenofovir alone or tenofovir plus emtricitabine) as an HIV prevention 

method. If either regimen is found to be effective, it would give women an HIV prevention 

method they can control, and would increase the number of prevention tools available to 

curb the epidemic. (NIAID) 

Reference: 

http://www.niaid.nih.gov/news/newsreleases/2009/pages/voice.aspx 

HIV Prevention during Pregnancy 

NIAID is examining the safety of HIV prevention regimens during pregnancy, when women 

are more susceptible to HIV infection. A small Phase I study of tenofovir vaginal gel among 

healthy pregnant women found no safety concerns. An HIV Prevention Agent Pregnancy 

Exposure Registry (also known as EMBRACE) is enrolling women who become pregnant during a microbicide or PrEP trial, or who have had planned exposures to drugs in pregnancy 

safety studies. The babies resulting from these pregnancies will also be enrolled. If studies can 

demonstrate safety for the mother and infant, the women will be able to continue participating in large trials testing the efficacy of these prevention strategies. (NIAID) 

Prevention of Mother-to-Child Transmission (MTCT) of HIV 

In 1994, a landmark study cosponsored by NIAID demonstrated that the drug AZT, given 

to HIV-infected women who had little or no prior antiretroviral therapy, reduced the risk of 

MTCT by two-thirds. This and other findings have helped reduce perinatal HIV infections in 

the United States by more than 90 percent, according to the Centers for Disease Control 

and Prevention. 

99
In 1999, a NIAID-funded study in Uganda found that single oral doses of the inexpensive 

drug nevirapine—one dose given to an HIV-infected mother at the onset of labor and one 

given to the infant soon after birth—reduced MCTC by nearly 50 percent. The World Health 

Organization now recommends this simpler, lower-cost regimen as a key component of 

MTCT prevention programs in resource-limited settings. Similar studies conducted by NICHDsupported researchers from Thailand, France, and the United States showed that transmission 

of HIV from a mother to her child can be reduced with shorter treatments of the drug AZT 

(zidovudine) at one-fifth the usual cost (in U.S. dollars). (NIAID and NICHD) 

Iron Supplementation in HIV-infected Pregnant Women 

Anemia is a major health problem in sub-Saharan Africa, affecting 35 to 75 percent of pregnant women, and is an important cause of maternal morbidity and mortality, fetal loss, and 

low birth weight. As part of a strategy to prevent anemia and its adverse effects, the World 

Health Organization recommends routine use of iron supplementation in all pregnant women 

living in areas with high prevalence of iron deficiency. However, there is little evidence showing 

that this intervention is effective in HIV-infected pregnant women, and some evidence suggesting that iron supplementation may increase the risk and density of malaria infection and 

be associated with increased viral load in these women. NIH-supported investigators are conducting a cross-sectional study of HIV-infected Malawian women in their third trimester of 

pregnancy to compare the prevalence of maternal anemia, the presence of malaria-associated 

parasites, viral load, and concentrations of certain blood markers among women who do and 

do not receive iron supplementation. Results from this study will inform standard clinical 

practice with regard to iron supplementation in this vulnerable population. (ODS) 

Antiretroviral Drug Use during Pregnancy by HIV-infected Women does Not 

Result in an Increase in the Risk of Birth Defects 

Antiretroviral drugs are routinely recommended for use during pregnancy to prevent the perinatal transmission of HIV. In addition, millions of HIV-infected women of childbearing age 

require antiretroviral therapy for their own health and may conceive while taking antiretroviral drugs. The safety of these drugs, especially regarding the potential for birth defects after 

exposure during early pregnancy, is often unknown. Using data from the Women and Infants 

Transmission Study, researchers assessed data from women who were enrolled during pregnancy and followed them and their infants over time. The rate of birth defects was compared 

among infants born to women with no antiretroviral exposure, with exposure only during the 

second and third trimester after the formation of the organs was almost complete, and with 

first-trimester exposure. The reassuring results showed no increase in overall risk of defects 

with first-trimester compared with later or no exposure. Major defects such as neural tube 

defects or heart defects were not increased with drug exposure. One defect, hypospadias, 

was potentially increased after first-trimester zidovudine exposure, and these data must 

be verified. However, overall data are reassuring to providers and patients who require 

antiretroviral therapy during pregnancy. Continued evaluation of the safety of newer 

antiretroviral agents in pregnancy is required. (NICHD) 

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Reference: 

Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, Vajaranant M, Diaz C, Tuomala R, 

Thompson B. Assessment of birth defects according to maternal therapy among infants in the 

Women and Infants Transmission Study. J Acquir Immune Defic Syndr. 2007 Mar 1;44(3):299-305. 

HIV Risk Reduction Interventions Tailored to Hispanic Women 

The University of Miami NCMHD Center of Excellence is conducting a three-year experimental study evaluating the effectiveness of a randomized HIV risk reduction intervention led by 

Hispanic women and culturally tailored to the specific needs of Hispanic women, who are 

disproportionally impacted by HIV/AIDS. The research study evaluates the effectiveness of a 

refined and culturally tailored specific intervention to increase HIV prevention behaviors for 

inner-city Hispanic women and explores the role of acculturation, family, stress, and family 

functioning as risk and/or protective factors in the prevention of HIV/AIDS among Hispanic 

women. (NCMHD) 

Interventions to Reduce HIV Risk and Improve Outcomes for Pregnant 

African-American Women 

The Virginia Commonwealth University (VCU) Center of Excellence in Health Disparities 

Research (CoEHDR) is conducting research on adverse pregnancy outcomes for AfricanAmerican women and community health education interventions that increase safe-sex 

skills development among pregnant women at high risk for HIV infection. (NCMHD) 

OAR-sponsored Research Activities 

As an Office within the Office of the Director, NIH, OAR has convened, sponsored, or supported a number of activities to focus increased emphasis on microbicide research and to 

enhance research and prevention efforts in women and girls. These include, but are not 

limited to: 

• Convened an Office of AIDS Research Advisory Council consultation on HIV prevention 

research for women and girls that outlined the research gaps and priorities that inform 

current NIH research. 

• Established the Microbicides Research Working Group, an external group of expert 

advisors that provides guidance to NIH and the research field. 

• Supports the Women’s Research Institute, a group of external experts who meet 

annually to outline the important gaps in research on women. 

• Convenes and chairs the Trans-NIH Microbicide Research Coordinating Committee 

composed of representatives from relevant NIH Institutes and Centers; and convenes 

and chairs the Trans-U.S. Government (USG) Microbicides Research Coordinating 

Committee including representatives from CDC, USAID, FDA, and DoD to share 

information, and facilitate collaboration, cooperation, and the efficient use of 

resources. This group will play a critical role in defining the next steps in USG 

microbicides research in response to the success of the first antiretroviral-based 

microbicide study (CAPRISA 004). 

101
• Provides support for NIH-funded studies in the prevention of mother-to-child HIV 

transmission, microbicide trials, and the pathogenesis of HIV in women. 

• Provides funding for and works with ORWH, NIAID, NICHD, and NIMH to implement 

an innovative microbicide research initiative designed to facilitate advancement in 

the field. The “Microbicides Innovation Program” provides funding to researchers 

with unique ideas that will further the science of microbicides research. Thus far, 

the MIP has funded 15 grants that address pressing scientific questions in microbicides 

development research. 

• Provides support to the Microbicides Trials Network to conduct the first assessment of 

the impact of the use of ARV-based microbicides in clinical trials on the level of ARV 

resistance in communities and the first studies of the safety of antiretroviral-based 

microbicides used during pregnancy (OAR) 

102
Rare Diseases 

A rare disease is a condition that affects fewer than 200,000 people in the United States. Several rare diseases are known to proportionately affect women more than men. It is not known 

how many diseases affect women more than men. The following paragraphs provide a summary of research and research-related activities that have been supported by ORDR that relate 

to conditions that are known to affect women more than men. 

THE RARE DISEASES CLINICAL RESEARCH NETWORk 

Since FY 2003, ORDR has collaborated with NIH Institutes and Centers to support the 

Rare Diseases Clinical Research Network (RDCRN). The RDRCN is made up of 19 distinctive 

consortia that are working in concert to improve availability of rare disease information, 

treatment, clinical studies, and general awareness for both patients and the medical 

community. The RDCRN also aims to provide up-to-date information for patients and to 

assist in connecting patients with advocacy groups, expert doctors, and clinical research 

opportunities. A listing of consortia and diseases or disorders studied by each can be 

found at http://rarediseasesnetwork.epi.usf.edu/. (ORDR) 

Rett Syndrome 

Rett syndrome is known to affect girls almost exclusively. The course of Rett syndrome, 

including the age of onset and the severity of symptoms, varies from child to child. Before 

the symptoms begin, however, the child appears to grow and develop normally. Then, gradually, mental and physical symptoms appear. Hypotonia (loss of muscle tone) is usually the 

first symptom. As the syndrome progresses, the child loses purposeful use of her hands and 

the ability to speak. Other early symptoms may include problems crawling or walking and 

diminished eye contact. The loss of functional use of the hands is followed by compulsive 

hand movements such as wringing and washing. The onset of this period of regression is 

sometimes sudden. The consortium, of which the study of Rett syndrome is an important 

part, is now in its second five-year cycle and focuses on a natural history study to establish 

a phenotype-genotype correlation over a broad spectrum of Rett syndrome phenotypes 

including the longitudinal pattern of progression of clinical features, quality of life, and 

longevity across this cohort. (ORDR) 

Congenital Adrenal Hyperplasia 

The most common form of congenital adrenal hyperplasia (CAH) results from a deficiency of 

the enzyme 21-hydroxylase. There are two forms of 21-hydroxylase congenital adrenal hyperplasia, a severe form termed “classical CAH,” with profound 21-hydroxylase deficiency, and 

a mild form called “nonclassical CAH,” which has a lesser deficiency of 21-hydroxylase. The 

classical form of CAH may be life-threatening if untreated. 21-hydroxylase deficiency in the 

classical forms, both salt-wasting and simple virilizing, results not only in reduced secretion of cortisol but also increased secretion of male-like hormones from the adrenal glands. 

These male-like hormones masculinize the female fetus in utero so that the genitalia are 

103
ambiguous. CAH can be diagnosed prenatally following amniocentesis or chorionic villus 

sampling. Classical CAH can be treated prenatally to prevent masculinization of the genitalia of affected females. 

11b-hydroxylase deficiency is the second most common form of CAH. Like 21-hydroxylase 

deficiency, it causes masculinization in the female fetus, but it also cause high blood pressure. It is diagnosed by hormone testing and DNA analysis and is treated by steroid hormone 

replacement. Like 21-hydroxylase deficiency, it can be prenatally diagnosed and treated, and 

has severe and mild forms. Studies to date have included a natural history study; a study to 

determine whether differences in other genes can modify the clinical course of adults with 

congenital adrenal hyperplasia due to 21-hydroxylase deficiency; and long-term outcome in 

offspring and mothers of dexamethasone-treated pregnancies to determine whether prenatal treatment with dexamethasone has any long-term effects on those who were treated as 

fetuses and who are now 12 years and older. (ORDR) 

Lymphangioleiomyomatosis 

Lymphangioleiomyomatosis (LAM) in a sporadic form affects almost exclusively women of 

childbearing age. LAM is typically slowly progressive. Treatments include the use of mTOR 

inhibitors (e.g., sirolimus), farnesyl transferase inhibitors, specific estrogen antagonists, 

endothelin receptor antagonists (e.g., Bosentan), statins (e.g., simvastatin), tyrosine kinase 

inhibitors (e.g., Gleevec), metalloproteinase inhibitors, and angiogenesis inhibitors (e.g., Avastin). When pulmonary function is no longer sufficient, a lung transplant may be needed, 

though the transplanted lung may eventually also be affected. The consortium assessed the 

safety of sirolimus administered orally or a placebo to assess the effect of sirolimus on biological and clinical markers of lung function, including spirometry findings, dyspnea, quality of life, 

lung volume, diffusion, oxygenation, and exercise tolerance. (ORDR) 

Progressive Familial Intrahepatic Cholestasis 

Progressive Familial Intrahepatic Cholestasis (PFIC) is passed from parents to children 

through genes. For a child to get PFIC they must receive two changed copies of a gene, one 

each from the mother and the father. These changes in genes are called mutations. Carrying 

one changed copy of a gene and one normal copy of a gene does not usually cause disease 

and is relatively common. Thus, parents of children with PFIC usually have no liver or other 

medical problems. One exception to this may be that women with one changed PFIC gene 

may develop liver disease during pregnancy. The purpose of a longitudinal study of genetic 

causes of intrahepatic cholestasis was to learn about the natural history and progression of 

PFIC and three other cholestatic liver diseases. (ORDR) 

Takayasu Arteritis 

Takayasu arteritis (TAK) is a rare form of vasculitis affecting medium-sized and large blood 

vessels, primarily the aorta. TAK generally affects people in their teens, twenties, or thirties, 

and primarily strikes young women. It is also more common in Asia. The cause of Takayasu 

arteritis is unknown. Inflammation of the large blood vessels may cause segments of vessels to weaken and stretch, resulting in an aneurysm (weakening of the vessel wall) or, more 

commonly, the inflammation of the vessel wall leads to thickening and subsequent partial 

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blockage or complete blockage of the artery. These blockages can result in the surrounding tissues being deprived of an adequate blood supply, which causes mild to very severe 

problems including cramping in the arms and legs, kidney damage with severe hypertension, 

strokes, or heart attacks. Many other symptoms and problems can be seen in TAK, including 

joint pains, fevers, and fatigue, among others. Three studies are currently under way: a longitudinal protocol for TAK (http://rarediseasesnetwork.epi.usf.edu/vcrc/takeaction/studies/ 

TAK-5503.htm); an imaging protocol for magnetic resonance (MRI) and positron emission 

tomography (PET/CT) in TAK(http://rarediseasesnetwork.epi.usf.edu/vcrc/takeaction/studies/TAK-5515.htm), and a comparison of x-ray-like tests that are not a part of regular medical 

care (PET/CT) with x-ray-like tests that are a part of a regular care (MRI). The third study will 

determine if the medication abatacept is safe and effective in Takayasu arteritis as well as in 

giant-cell arteritis. (ORDR) 

Antiphospholipid Antibody Syndrome 

Antiphospholipid antibody syndrome (APS) is an autoimmune disease, and 75 to 90 percent 

of people affected with this disease are women. In this disorder, antibodies that are found in 

the blood and normally fight off infections instead turn against the body’s own normal clotting mechanisms. These antibodies make people more prone to certain problems, such as clots 

in the deep veins in the arms and legs, known as deep vein thrombosis (DVT), or in the lung, 

known as pulmonary embolism (PE). People with APS can also develop clots in their arteries 

that can cause heart attacks or strokes. In certain women, these antibodies can cause recurrent pregnancy loss. The treatment of choice for patients with APS who have had a blood clot 

is anticoagulant therapy (treatment with a blood thinner). For women with APS and recurrent 

miscarriages who have not had a prior blood clot, the use of anticoagulant therapy during the 

pregnancy may increase the likelihood of a successful outcome. Some individuals may have 

elevated antiphospholipid antibodies but have no clinical manifestations of the syndrome. 

These individuals do not need anticoagulant therapy, but studies are ongoing to evaluate 

whether an aspirin a day might be beneficial for these individuals. Diagnostic and/or therapeutic limitations exist and prospective studies have begun to more clearly define the syndrome 

and develop better therapies. (ORDR) 

Thrombotic Thrombocytopenic Purpura 

Thrombotic thrombocytopenic purpura (TTP) is a rare blood condition characterized by a 

low platelet count and the widespread formation of small blood clots throughout the circulatory system. Platelets are the smallest of the cells in the blood, and they function as tiny corks 

that form a plug to stop bleeding. In general, a very low platelet count, referred to as thrombocytopenia, is associated with bleeding problems, and these patients may present with large 

bruises. These patients can also develop clotting complications involving the brain, kidneys, 

and virtually any organ in the body. 

TTP occurs more frequently in women than in men. The primary treatment for TTP is a process called “plasma exchange,” during which a patient’s plasma (the liquid part of the blood) 

is removed and replaced with plasma from blood donors. This treatment is very effective 

and life-saving in the majority of patients. Other treatments that have been used include steroids, aspirin, and certain chemotherapy agents. In a subset of patients, TTP may recur after 

105
stopping treatment. These patients may require treatment to be restarted, or a different 

type of therapy may become necessary. The study of incidence of thromboembolic events in 

patients with antibodies to heparin-PF4 after cardiac bypass was begun to determine how 

often heart surgery patients who receive heparin develop an immune response (heparininduced thrombocytopenia) that leads to clots forming in different parts of the body. 

GENETIC AND RARE DISEASES INFORMATION CENTER 

ORDR supports, with the National Human Genome Research Institute, the Genetic and Rare 

Diseases Information Center (GARD). GARD provides information to patients and their families, health professionals, researchers, and the public. A customer service satisfaction survey 

showed that, typically, information center customers are white, non-Hispanic, English-speaking women between the ages of 31 and 40 with a postgraduate education who request 

information for themselves and for family members or friends, who could be male or female. 

To reach an even wider audience, GARD now focuses on making available questions and 

answers on the ORDR Web site in addition to services by e-mail, telephone, or mail. In 2010, 

the GARD section of the ORDR Web site has receive an average of 75,000 visits per month in 

addition to continued inquiries by e-mail, telephone, and mail totaling over 27,000 since its 

inception. (ORDR) 

SCIENTIFIC CONFERENCES 

ORDR collaborates with Institutes, Centers, and Offices at NIH to stimulate rare diseases 

research by cosponsoring scientific conferences where research is lagging or to take advantage of scientific opportunities. Throughout the years, conferences cofunded by ORDR with a 

focus on women’s health have included: 

•	�Profiling of Immune Response to Guide Cancer Diagnosis, Prognosis, and Prediction of 

Therapy, which included sessions on T-regulatory T cells as predictors of survival in ovarian cancer and Interleukin-6 polymorphism as predictor of outcome in high-risk breast 

cancer. The meeting highlighted the clinical significance of immunologically regulated 

molecules as markers and validation approaches for basic and clinical researchers interested in marker development. 

•	�The Status and Future of Acupuncture Research: 10 Years Post-NIH Consensus Conference, 

which synthesized the current status of the research evidence base for the efficacy of 

acupuncture for a number of diseases, including rare diseases, through plenary sessions, 

breakout sessions, and workshops. Overall, the goal was to strengthen the evidence base 

for acupuncture therapy. Sessions included Acupuncture in Female Infertility–Basic and 

Clinical Studies and Functional Neuroimaging of Acupuncture in Fibromyalgia: Insights 

into Mechanisms and Clinical Trial Design. 

•	�Stillbirth Definition and Classification System: Developing an International Consensus, 

which gathered international experts and researchers to address the definition of 

stillbirth, the goals of a stillbirth classification system, and the necessary criteria for 

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assigning cause of death. The development of an agreed-upon classification system 

should facilitate analyses of larger amounts of stillbirth information with greater sample 

sizes, allowing for more robust conclusions from the international research currently conducted on stillbirth. 

•	�2010 NHLBI/LAM Foundation International Lymphangioleiomyomatosis) Research, 

which reviewed research developments in lymphangioleiomyomatosis, aimed to attract 

new investigators to LAM research, identified promising new LAM research directions, 

and attempted to reach consensus on difficult clinical issues. The 2010 LAM Research 

Conference was needed to sustain the momentum that has brought the LAM field in 

a relatively short time from obscurity to trials based on molecular targets. The advances in understanding of the molecular and cellular basis of the disease have been 

remarkable, and the basic science community, the clinical science community, and LAM 

patients are all aligned to continue to address this problem in an aggressive, cooperative, and intelligent manner. The 2010 LAM Research Conference charted the course for 

new research directions in LAM, assisted the clinical community in arriving at consensus 

on the optimal management of LAM, and continued to provide hope to women affected 

by this ravaging disease. 

• The 2007 LAM Foundation Lymphangioleiomyomatosis International Research Conference brought together basic scientists working in different disciplines pertinent to 

lymphangioleiomyomatosis with pharmaceutical experts from industry, clinical investigators, patients, and other advocates to advance research on understanding and treating 

LAM. The ultimate goal was to identify new targets for therapeutic interventions. 

•	�Mental Health Promotion and Injury Prevention in the Context of a Diverse, Transforming 

China addressed issues including: (1) risk factors for suicide and injury mortality in Chinese women, (2) the implications of rapid economic and technological development for 

risk of suicide and injury in men and women, and (3) ethnic differences. 

•	�Orphan Mechanisms of Primary Ovarian Insufficiency: Passion for Participatory Research. 

Galactosemia is a rare metabolic disorder that is associated with the development 

of primary ovarian insufficiency. Despite appropriate dietary restriction of galactose, 

many girls and young women develop primary ovarian insufficiency. Participants addressed mechanisms of ovarian toxicity related to galactosemia, induction of puberty in 

girls with galactosemia who have primary ovarian insufficiency, hormone replacement 

in women with galactosemia who have primary ovarian insufficiency, mental health aspects of primary ovarian insufficiency as it relates to galactosemia, and pregnancy in 

women with galactosemia. 

•	�Cognitive and Neuroplastic Changes Following Surgical Hemispherectomy and In Utero 

Strokes Affecting an Entire Hemisphere. The main goal of this conference was to ascertain the state of the art in hemispherectomy outcome as a precursor to preparing 

a protocol to test a number of assumptions. To that end, leading neurologists, neurosurgeons, and cognitive neuroscientists were invited to discuss their experience with 

patients receiving hemispherectomies. 

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• The Preconception Care Research: Improving Birth Outcomes and Reproductive Health 

Conference, which brought together a broad spectrum of experts, including clinicians 

and basic and behavioral scientists, to define a multidisciplinary framework for developing a research agenda in preconception care research. 

•	�Opsoclonus Myoclonus Syndrome (OMS) Workshop. This disease is also more prevalent 

in women than in men. The goals of the OMS Workshop were to discuss the various issues and special challenges associated with the diagnosis, prognosis, and treatment of 

OMS; identify strategies to improve research and clinical collaborations and resource 

sharing in the United States and internationally; examine the disease course of pediatric 

and adult-onset OMS; discuss current therapeutic strategies; and look at immune mechanisms of OMS. The Workshop resulted in identification of basic and clinical research 

needs and setting of research priorities, and is expected to facilitate the development 

of clinical protocols. 

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National Toxicology Program
�

The National Toxicology Program, an interagency testing program headquartered at NIEHS, 

has listed more than 40 chemicals in its Report on Carcinogens because they have been found 

to cause tumors in laboratory animals. These include pharmaceutical products such as diethylstilbestrol, a synthetic form of estrogen that was used to prevent miscarriages, chemical 

solvents and flame retardants, and a variety of chemicals used in the manufacturing of dyes, 

rubber, vinyl, and polyurethane foams. (NIEHS) 

Reference: 

http://ntp.niehs.nih.gov/ 

109
Genetic Determinants of Sex
�

Sex Determination: More Subtle and More Precise Than Previously Thought 

The Drosophila doublesex gene, a component of the genetic hierarchy that determines sex, 

is transcribed differently in males and females. The simplest model for how doublesex works 

is that downstream genes are repressed by male-specific doublesex transcripts and activated 

by female-specific doublesex transcripts, or vice versa. Although some genes are regulated 

in an “all or nothing” way by doublesex, a University of Southern California team discovered 

that most genes regulated by doublesex are expressed at different levels in males and females, 

rather than being on in one sex and off in the other. The team also demonstrated that many 

genes are expressed at different levels in males and females only during very limited periods 

during development. It would not be surprising if the conclusions drawn from these findings— 

that differences in gene expression that determine sex are more subtle and more ephemeral 

than previously thought—were also applicable to human sex determination, since the process 

in humans is also determined by a gene hierarchy, some components of which are expressed 

differently in males and females. (NIGMS) 

Reference: 

Lebo MS, Sanders LE, Sun F, Arbeitman MN. Somatic, germline and sex hierarchy regulated 

gene expression during Drosophila metamorphosis. BMC Genomics. 2009 Feb 13;10:80. 

X Chromosome Genes More Active, Variable in Females 

An analysis of the female X chromosome has led to surprising results showing that not only 

are genes on this bundle of DNA more active than once thought, but that their activity patterns vary greatly from woman to woman. Through sequencing, scientists have found that the 

X chromosome contains 1,098 protein-coding genes, compared with the male Y chromosome’s 

78. With females having a double dose of X-linked genes (they have two X chromosomes 

while males have an X and a Y), researchers have long believed that most genes on one of 

the X chromosomes are inactivated. But researchers have now shown that at least 15 percent 

of an X chromosome’s genes escape this inactivation. The researchers also found that gene 

activity varies greatly from woman to woman. This new information could lead to a better 

understanding of individual health differences, as well as the 300-plus diseases linked to the X 

chromosome. (NIGMS) 

Reference: 

Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005 Mar 17;434(7031):400-4. 

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Additional NIH Resources
�

NIH OFFICE OF RESEARCH ON WOMEN’S HEALTH 

The Office of Research on Women’s Health, established in September 1990 within the 

Office of the Director, NIH: 

(a) Advises the NIH Director and staff on matters relating to research on 

women’s health
�

(b) Strengthens and enhances research related to diseases, disorders, and 

conditions that affect women
�

(c)	� Ensures that research conducted and supported by NIH adequately addresses 

issues regarding women’s health 

(d) Ensures that women are appropriately represented in biomedical and 

biobehavioral research studies supported by NIH
�

(e)	� Develops opportunities for and supports recruitment, retention, re-entry, 

and advancement of women in biomedical careers 

(f)	� Supports research on women’s health issues. 

ORWH works in partnership with the NIH Institutes and Centers to ensure that women’s 

health research is part of the scientific framework at NIH and throughout the scientific 

community. ORWH works collaboratively with the Advisory Committee on Research on 

Women’s Health, which comprises physicians, scientists, and other health professionals; 

and the Coordinating Committee on Research on Women’s Health, which is composed 

of the NIH Institute and Center directors or their designees. 

ORWH, in collaboration with NIH and the extramural scientific and public advocacy 

communities, has undertaken strategic planning and the resulting publication is entitled, 

Moving into the Future With New Dimensions and Strategies: A Vision for 2020 for 

Women’s Health Research. 

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WOMEN’S HEALTH RESOURCES WEB PORTAL 

The NLM Division of Specialized Information Services, Outreach and Special Populations 

Branch has partnered with ORWH to create the Women’s Health Resources Web Portal 

(http://www.womenshealthresources.nlm.nih.gov). This portal gives researchers and 

consumers access to the latest information in a centralized location about significant topics in 

women’s health from scientific journals, peer-reviewed sources, NIH Institutes and Centers, and 

health news sources. The portal focuses on health topics and the NIH Priorities for 

Women’s Health to identify research initiatives and overarching themes. The Health 

Topics section is organized by disease or condition categories, and an A to Z index is 

available to provide consumers with an easy way to locate specific health topics. The NIH 

Priorities for Women’s Health section is created from the annual recommendations put 

forth by the CCRWH and ACRWH. The topics for this section include lifespan, sex/gender 

determinants, health disparities/differences and diversity, and interdisciplinary research. 

NLM has created specific user-friendly strategies for these topics to ease searching within 

ClinicalTrials.gov and PubMed. The portal is also using social media to connect with the 

public for health awareness campaigns. (NLM) 

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Appendix: NIH Reports on ORWH and NIH Support for Research on Women’s Health 

NIH Support for Research on Women’s and Men’s Health Issues: FY 1988, 1989, 1990.

NIH Support for Research on Women’s and Men’s Health Issues: FY 1991 and 1992.

NIH Support for Research on Women’s Health Issues: FY 1993-1994.

Report of the Office of Research on Women’s Health and of NIH Support for Women’s Health 

Issues: FY 1995-1996.

Report of the Advisory Committee on Research on Women’s Health: Office of Research on 

Women’s Health and NIH Support for Research on Women’s Health Issues: FY1997-1998. 

Report of the Advisory Committee on Research on Women’s Health: Office of Research on 

Women’s Health and NIH Support for Research on Women’s Health Issues: FY1999-2000. 

Report of the Advisory Committee on Research on Women’s Health: Office of Research on 

Women’s Health and NIH Support for Research on Women’s Health Issues: FY2001-2002. 

Report of the Advisory Committee on Research on Women’s Health: Office of Research on 

Women’s Health and NIH Support for Research on Women’s Health Issues: FY2003-2004. 

Report of the Advisory Committee on Research on Women’s Health: Office of Research on 

Women’s Health and NIH Support for Research on Women’s Health Issues: FY2005-2006. 

Report of the Advisory Committee on Research on Women’s Health: Office of Research on 

Women’s Health and NIH Support for Research on Women’s Health Issues: FY2007-2008. 

To order copies of ORWH reports or other ORWH publications go to http://orwh.od.nih.gov/ 

pubs.html 

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NIH Publication No. 10-7606-D