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Reshaping Women's Health Research

Painting of women by Victoria FlaniganArticle by Alicia P. Gregory
Artwork by Victoria Flanigan

How would you rate the amount of stress you are currently under: small, moderate, large, overwhelming?

How would you describe your current weight: too low, about right, a little overweight, fat, obese?

Do you have any form of diabetes?

Have you ever had migraines, cluster headaches, tension headaches?

Have you had excessive anxiety or worry?

Have you ever felt, or has anyone ever suggested, that you were a problem drinker?

Has an intimate partner hit, kicked, punched, or otherwise hurt you?

These are just a few of the questions the University of Kentucky is asking women in a program unveiled in March 2006 called the Kentucky Women’s Health Registry. The registry is a comprehensive online survey open to all women. And Leslie Crofford, director of UK’s Center for the Advancement of Women’s Health, emphasizes, “You don’t even have to be seen by a doctor at UK. You just report to us the information you want to give, and it will help us learn how to better care for Kentucky women and give interested women the chance to participate in medical research.”

The Kentucky Women’s Health Registry is just one UK initiative targeting women’s physical and mental wellness. The Center for the Advancement of Women’s Health is combining research, clinical care, training, and outreach to offer women one-stop shopping when it comes to their healthcare. Other important, multidisciplinary efforts, like the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) program and the Center of Biomedical Research Excellence (COBRE) in Women’s Health, train and support research faculty. And UK’s innovative Center for Research on Violence Against Women is working to improve women’s safety and access to help after victimization.
UK scientists and scholars who are advancing women’s health research through these and other ongoing projects focused on women currently have attracted $112.5 million in funding.

Creating a Women’s Health Registry
Why do we need the Kentucky Women’s Health Registry? Crofford answers this question with a few of her own: “Why do some diseases affect women more than men? Why do women respond to some drugs and therapies differently than men? What environmental factors and behaviors most influence women’s health?

“We don’t know. But we want to find out. And we need the help of women of all ages and races across Kentucky,” Crofford says. Her enthusiasm about the registry and eagerness to spread the word is evidenced by recent road trips to county agricultural extension and health department offices. “I wanted to meet face-to-face with the people who work on a daily basis with the women in their communities,” Crofford says, adding that she’s asking these county workers to put up posters and refer women to the Internet survey or hand out paper surveys.

Statewide radio spots, billboards and targeted recruitment efforts in Eastern and Western Kentucky, as well as in the African-American and Hispanic communities, are some of the ways Crofford hopes to enroll 2,500 women in the registry in its first year. Over the next 10 years, she hopes to collect data from 25,000 Kentucky women.

With questions ranging from demographics, financial issues, health-care access, chronic symptoms, medical diagnoses, and domestic violence, the Kentucky Women’s Health Registry survey is uniquely comprehensive. “Other states, like Michigan, where I worked last, have surveys, but we designed ours to be much broader,” says Crofford, who came to UK in October 2004.

“The breadth of information will allow us to see how individual health behaviors affect overall health. Many women haven’t been educated or haven’t internalized the things we know about what promotes good health—maintaining a healthy weight, getting the recommended amount of exercise, managing stress, not engaging in risky sexual behavior, not smoking or drinking to excess. When you look closely, women don’t have just one of these issues,” she says. “For example, they smoke and have a sedentary lifestyle, or drink and engage in risky sexual behaviors.

“The information we get from this survey will help us understand how these behaviors relate to one another, allow us to identify things that promote unhealthy lifestyle choices and create targeted programs to help women change these behaviors.”

The enormity of this challenge is not lost on Crofford. “It’s not an easy thing to do, but my own belief is that if you change women’s behaviors, you can change family behaviors.” She grins and says, “We do most of the shopping and cooking, right?

Photo of Leslie Crofford with registry billboardLeslie Crofford, director of the Center for the Advancement of Women’s Health, led the creation and marketing (including this billboard in downtown Lexington) of the Kentucky Women’s Health Registry. This online survey will collect health information from female volunteers over the next 10 years to track health trends and serve as a recruitment tool for clinical trial participants.

“We need to understand the barriers to change, and then be able to provide the encouragement and training to allow women to take charge of their health.”

And part of that take-charge attitude, Crofford adds, beyond an interest in their own health and the health of their families, is a desire to contribute to the health of women everywhere by taking part in medical research. Wendy Baldwin, UK executive vice president for research, says, “Over the past few years there has been an increased effort to include women in clinical trials and to analyze the data to test for gender differences. We are finding many situations where men and women present with different symptoms, have different courses of illness or react differently to medications.”

A Food and Drug Administration report, “Equality in Clinical Trials: Drugs and Gender,” says, until recently, women were not routinely included in safety and efficacy tests of new drugs for their own protection, “since there was often no way to be sure that a woman was not pregnant or that the drug might not cause some problem that might interfere with future pregnancies. In addition, it was thought that women’s hormonal cycling or other factors peculiar to being female might constitute variables that could skew trial results.”

Researchers used to assume that disparity in height, weight and hormones explained why men and women react differently to the same drug, but two studies in 1996 painted a more complicated picture.

In the first study, women woke up almost twice as fast (7 minutes versus 13 minutes) from anesthesia as men, and weight had nothing to do with it. The other study showed that a painkiller worked twice as well for women than men who had their wisdom teeth removed, even when body size and menstrual cycle were factored in.

Baldwin notes, “A national push to include more women in clinical trials will help answer these questions and truly make medicine better targeted for all people.”

Crofford says, “We created the Kentucky Women’s Health Registry to streamline the process of linking up women who want to participate in medical trials with researchers who need their help.”

Charcoal sketch of pregnant belly and hands by Victoria FlaniganScientists will face a review process (led by the Center for the Advancement of Women’s Health) to gain access to women in the registry. “It’s not like any Tom, Dick or Harry can come in and say, ‘I’d like to get patients out of your registry to do X.’ That’s not good enough. The research study has to be focused, spell out why women are going to be studied, and the researchers have to agree to do gender-specific data analysis so that the effect of X on women is clear.

“Because we want to be able to track changes in health over time,” Crofford says, “we’ll send annual reminders to women to retake the survey.” Registry participants will also receive health information updates and access to clinical trials of new therapies for conditions that affect them. “You agree to be contacted as part of filling out the survey, but participation in clinical trials is your choice,” she says.

Advancing Women’s Health
The Center for the Advancement of Women’s Health began in 1999 (under the moniker of the Women’s Health Center) and the first director, Deborah Kwolek, made a lasting impact on UK. She received a grant to incorporate gender-specific issues into the curricula of the colleges of allied health, dentistry, medicine, nursing, and pharmacy. The curricular elements she helped create are now standard training for UK health students. For example, gender differences in drug metabolism (there are significant differences between men and women in the way drugs are absorbed, distributed and concentrated in the bloodstream) were incorporated into pharmacy courses. And students train with patient scenario role-playing (with actors portraying patients with, for instance, head and neck trauma associated with domestic abuse).

In 2000, a group of female community leaders rallied behind the Women’s Health Center. Led by Mira Ball (a UK Trustee, chief financial officer of Ball Homes Inc., and former Fayette County public school teacher), these women raised the funds to endow a chair for the center director, named for former first lady of UK Gloria Singletary. “They had the enthusiastic participation of Gloria herself,” Crofford notes, adding, “She’s a champion of women’s health issues and an unbelievable lady.” Private donations were matched by funds from the state’s Research Challenge Trust Fund to create the chair.

Crofford’s own journey to UK began with a phone call from a former intern from Crofford’s residency days at Barnes Hospital in St. Louis. That call was from Anne Pittman, a UK associate professor in internal medicine, who had just been named to the search committee for the center director. “She knew my background,” Crofford says. (Crofford trained in molecular biology and held a rheumatology fellowship at the NIH, and was, at that time, a professor of rheumatology at the University of Michigan.)

Crofford studies fibromyalgia—chronic, widespread muscle pain, accompanied by fatigue. In 2005 the journal Arthritis & Rheumatism published her study on Pfizer’s drug Lyrica™, which was shown to significantly reduce the pain of fibromyalgia and improve sleep. “The inflammatory stress-related diseases I study are much more common in women, so when Anne was casting about for people she knew with a connection to women’s health, she found me.”

And what started as a search for one, became a dual recruitment. “I wasn’t so sure at first. My husband is also in academic medicine, and we were happy where we were. But Anne begged me to send her both of our CVs, which I did,” Crofford recalls. “And then the next thing we knew, Al Cohen, director of the UK Markey Cancer Center, was on the phone to my husband.” Kevin McDonagh, Crofford’s husband, became chief of hematology/oncology and deputy director of the Markey Cancer Center, and she became chief of rheumatology and director of the Center for the Advancement of Women’s Health in 2004.

Her first order of business, Crofford says, was helping the center “find its research legs” by recruiting an associate director for research. That role was filled by Sara Jo Nixon, a UK psychology professor who now spearheads the first of two research groups. Nixon’s group will design research projects to explore the interaction of different health behaviors (i.e., smoking, drinking, sedentary lifestyle) by examining the Kentucky Women’s Health Registry. Nixon has already been involved in such behavioral research—a National Institute on Drug Abuse project that began with the unlikely (and somewhat unpopular) premise that nicotine may have some positive effects for substance abusers. (For more, see Odyssey Summer 2004.)

Charcoal sketch of pregnant woman by Victoria FlaniganWomen's Health Statistics

Heart disease is the number one killer of women in the United States.

Colorectal cancer and breast cancer are the second- and third-leading cancer killers of women.

Women are more likely than men to die from a stroke.

Nearly twice as many women as men die from Alzheimer’s disease each year.

75 percent of Americans living with autoimmune disorders, including lupus, multiple sclerosis and rheumatoid arthritis, are women.

The second research group focuses on stress-related syndromes. “One of the things that became very clear once I got here was that UK has a huge amount of expertise in neuroendocrine immunology,” says Crofford, who will partner with Suzanne Segerstrom (psychology/optimism and immunity), Mary Duke (internal medicine/chronic fatigue), Deborah Erickson (urology/irritable bladder), Lisbeth Selby (gastroenterology/irritable bowel), Tarvez Tucker (neurology/UK Headache & Pain Clinic), Charles Carlson (psychology/orofacial pain), and Reny de Leeuw (dentistry/ orofacial pain).

The Center for the Advancement of Women’s Health targets UK students, as well. “We train students and residents in nursing, medicine and pharmacy in gender-specific issues related to their field. We have an internal medicine residency track in women’s health that allows us to target primary-care providers.”

The center also supports community outreach efforts, like Crofford’s own two-hour workshops on fibromyalgia. She sees the center’s outreach role expanding as other practitioners adopt similar formats for conditions like chronic fatigue and irritable bowel syndrome. “Although we know we can’t see every person individually in our clinic, the center can be a resource for women in the community who may or may not be patients at UK.”

The bottom line for her center, Crofford says, is helping women take charge of their own health before a devastating diagnosis. “By the time a woman gets to the Gill Heart Institute, she’s already had a heart attack. By the time she gets to the Markey Cancer Center, she’s already got cervical cancer. That’s too late. We know cervical cancer is associated with sexually transmitted disease. We know endometrial cancer has a strong link to obesity. Our job is to understand these modifiable risk factors and teach prevention.”

And that prevention takes the form of the Women’s Health Clinic. Shortly after her arrival on campus, Crofford secured dedicated space for this new multidisciplinary clinic on the second floor of the Kentucky Clinic. “We’ve always had good primary care, which is a strong partnership between College of Medicine M.D.s and College of Nursing ARNPs,” she says, but these primary-care providers used to see patients in an overcrowded internal medicine clinic. Now, women have a space all their own.

“In fact, this is for the clinic,” she says, pointing to a painting that, for the time being, hangs in her office. Muted gold and blue rectangles highlight the outline of a woman. Her head is back and her hand covers her breast. An X-ray view of her spine and pelvis shows the underlying strength of her form. “I commissioned this from a UK graduate student. She was exploring issues of body and acceptance. I think it’s important that we be conscious of the relationship between women and their bodies.” The artist, Victoria Flanigan, who created the cover of this magazine and artwork for this article, earned her master’s degree in fine arts at UK in May 2006.

Crofford’s goal for the clinic: create a one-stop shop for healthcare. “We don’t want women to have to make extra trips. We’ve added sub-specialists in rheumatology, gastroenterology, neurology, gynecology, and nutrition. We’ll soon have a nurse psychologist to see patients in our clinic and a staff member trained in the Cooper-Clayton smoking cessation program. By adding these sub-specialties and quality-of-life programs, we can better assist our patients in learning how to live healthy lives.”

Crofford adds, “We’re not duplicating UK programs that are great—like the Comprehensive Breast Care Center. It’s wonderful that the Markey Cancer Center and Gill Heart Institute are right here on campus. Our hope is that we fit nicely within the spectrum of clinical activities at UK.

“If we can intervene early, when women first develop symptoms of pain and stress, we can stop these things from mushrooming into huge, lasting problems 10 years down the road.”

Breaking the Cycle of Violence against Women
After leaving work at a salon in a Louisville, Kentucky, shopping mall, Mary Byron sat in her car as it warmed up. It was December 6, 1993, just weeks after her former boyfriend had been arrested and jailed for kidnapping and raping her. Mary thought she was safe. But she didn’t know her attacker had posted bail.

Mary’s former boyfriend approached her car and fired seven bullets into her head and chest. It was Mary’s 21st birthday.

“She had asked a number of different people in the local justice system to let her know if her attacker was released,” explains Carol Jordan, director of UK’s Center for Research on Violence Against Women, “but whatever the good intentions were of these professionals, that notice never came and her life ended that day.”

Mary’s horrific case led to the creation of VINE® (Victim Information and Notification Everyday), a 24-hour, automated phone and email system that updates victims on the custody status of offenders. VINE was first implemented in Jefferson County, Mary’s home county, one year after her death. Jordan, who has spent 23 years helping women and children who have faced sexual assault, intimate partner violence, child abuse, and stalking, co-authored legislation in 1996 to expand the system, making Kentucky the first state in the nation to offer a statewide victim notification system. Today more than 1,400 communities in 36 states offer VINE.

“VINE has literally saved lives,” Jordan says. “And Mary’s story also led to the creation of the Mary Byron Foundation, which funds innovative programs across the country that seek to break the cycle of violence against women. The foundation contributed $10,000 to the UK Center for Research on Violence Against Women when we started in 2002, and just last April gave us $50,000 to establish the Mary Byron Scholars Program, a graduate fellowship in her name.”

Charcoal sketch of women in reflective pose by Victoria FlaniganBefore coming to UK, Jordan spent eight years on the executive staff of former Governor Paul Patton, spearheading the state’s effort to address violence against women and children. Over her career she successfully lobbied for 30 pieces of legislation, including bills to improve mental health services, strengthen prosecution, expand civil remedies for victims, and to create innovative systems like VINE and Kentucky’s Amber Alert System. She secured the first state funding for rapecrisis centers and for children’s advocacy centers. With the Kentucky Domestic Violence Association, she increased state funds for domestic violence programs to $4.8 million, an increase of 112 percent. In 1996 she authored a resolution to encourage colleges and universities across Kentucky to increase curricula related to violence against women and children.

“I’m so pleased to now be here at UK and have a role in making that resolution happen,” says Jordan, her energy and passion for what she does evident with each word. Leslie Crofford, COBRE director Tom Curry and BIRCWH director Jef Ferguson all use the same word to describe Jordan: dynamic.

Why was such a center necessary? “During my time in the governor’s office, I realized police, advocates, therapists, physicians, and nurses were just not adequately prepared by their graduate coursework to identify violence in the lives of their patients or clients, or to know what course of action to take if abuse was disclosed. Our educational system was inadequate. And, as a nation, we lacked a research agenda on violence against women, which meant we weren’t doing enough research, and we were doing an inadequate job of putting good research in the hands of the professionals who need it.

“It is both a strength and a challenge that there is no discipline called ‘violence against women.’ It crosses traditional academic boundaries—psychology, law, social work, medicine, nursing, women’s studies, and more. That’s why an interdisciplinary approach is so important.”

The Center for Research on Violence Against Women was the brainchild of Jordan and former UK Provost Mike Nietzel. “We wrote a concept paper, and I took that to the governor and Mike took it to President Todd, so the center was really a partnership between the university and the governor’s office. Next, we created an advisory committee of faculty from all the disciplines I just mentioned to get input on what the center’s direction and focus should be.” After leaving the governor’s office, Jordan was recruited by UK to serve as the center’s first director.

The center’s national advisory committee is made up of faculty from prestigious universities across the country, Kentucky advocates and practitioners, and UK faculty associates from the colleges of arts and sciences (psychology), law, medicine (OB/GYN, psychiatry, behavioral science), nursing, social work, the women’s studies program, and the Center for the Advancement of Women’s Health.

“We have the potential to be a nationally preeminent center—something that is not duplicated anywhere in the country,” says Jordan, who in 2005 received the Paul H. Chapman Award from the Foundation for Improvement of Justice. The award recognizes innovative programs that can serve as national models. She says, “The fact that we have made reforms on behalf of women and children in Kentucky and that those reforms have been shared with the nation speaks not to what a single person has done, but to what the collective effort of people believing deeply in their work can create.”

Jordan donated the $10,000 check she received for this award to the center to support the creation of an endowed chair in mental health, a field she is particularly passionate about. Jordan spent three years as a clinical psychologist before becoming a policymaker.

“I believe we have the opportunity to create an unparalleled center on the empirical study of violence against women, because of the quality of the faculty already here, the prestigious faculty we plan to recruit, and because of the way our work has been embraced by the professional and academic community. We’re ready to do this on a grand scale by endowing five chairs of study on violence against women.” This immense fundraising effort—a minimum of $1 million per chair—will help UK become “the place where the top scientists publishing and researching in this area are located and where graduate students and faculty will want to be.”

Funding is already set for the first of the five chairs: the Verizon Wireless Chair of Studies on Violence Against Women will be established this year in the College of Medicine. Jordan credits Dean Jay Perman with influencing the selection of the College of Medicine as the academic home for the center’s first endowed chair. “His support has been substantial, and his insightful understanding of the impact of violence on a women’s health has been a great asset to our effort.” The center’s second chair will address women’s mental health. The other chairs will focus on children who witness violence, on the multicultural study of violence against women, and on forensic mental health.

Photo of Carol Jordan's research teamDirector Carol Jordan (center) and the staff of the Center for Research on Violence Against Women are involved in research projects focused on protective orders and sentencing decisions in domestic violence cases. From left to right: Emily Bradshaw and Emily Hodell (psychology doctoral candidates), Lana Stephens and Laurie Depuy (office staff), Danielle Duckett-Pritchard (second-year master’s student in sociology), and Adam Pritchard (sociology doctoral candidate).

The center also conducts its own research projects. (Learn how one of these projects, the 2004 Women’s Safety Study, had immediate impact on women at UK.)

A second study under way is analyzing trends in the issuance and service of domestic violence protective orders over the past decade. Jordan leads a third study, with Jim Clark, the associate dean for research in the UK College of Social Work, Bob Lawson in the College of Law, and Jonathan Golding in the Department of Psychology, that is investigating patterns in sentencing and parole board decisions in cases where victims of domestic violence kill the offender.

Jordan is also partnering with Tracey Corey, Kentucky’s chief medical examiner, on a fourth project to explore patterns of homicide in cases of intimate partner violence through a review of autopsy records of women who have been murdered.

While acknowledging the importance of these studies, Jordan emphasizes that the center's efforts at research go beyond its own studies. “If this center is the only unit on campus generating research related to violence against women, somebody ought to pack up my office and send me home, because I will have dismally failed at this job,” Jordan says emphatically. “It’s just as important for us to facilitate research by key faculty across campus as it is to do our own.” The center’s grant program has funded 11 faculty projects.
The center also sponsors scholarship: it is developing a graduate certificate, discipline-specific coursework, and currently employs four grad students in its research projects.

“The center’s mission is to advance research and graduate education on violence against women. What that means is we want to see state-of-the-art research move from the campus to the community—to the hands of the judge making a decision about probation for an offender, the therapist comforting a child, the doctor examining a patient, the police officer showing up at the scene of a domestic dispute.

“Because in a very real way,” Jordan says, “what our UK faculty explore and discover can be lifesaving. This is an exhausting and emotionally draining field to be in because you’re exposed to some of the most horrific cruelties that one person can perpetrate on another. But you also see the amazing resiliency of women and children. Violence clearly changes a woman’s life, but it need not ruin it. And as researchers and educators, we can play a role in ensuring it doesn’t.

“I remain, after 23 years in the field, a hopeless optimist.”

Charcoal sketch of pregnant woman by Victoria FlaniganViolence Statistics

Homicide is the leading cause of death among pregnant women in the United States.

In Kentucky, 1 in 9 women have been raped.

In 2000, the number of women shot and killed by an intimate partner equaled nearly one woman every day.

Domestic violence is the most common cause of injury to women age 15 to 44.

Estrogen: Protecting the Brain against HIV and Fighting Cardiovascular Disease
Women’s health research at UK ranges from bedrock topics—like pregnancy and breast cancer—to new fields, such as estrogen and HIV infection, and brain activation across the menstrual cycle. Tom Curry, director of the UK COBRE in Women’s Health, says the innovative research of two young faculty, who transitioned from the BIRCWH program to the COBRE program (see Career Building at UK) and are now well on their way to establishing long-term research careers, is answering and revealing new questions in areas that have yet to be explored.

Melinda Wilson, who earned a Ph.D. in molecular biology at Loyola University, says, “I came here from Chicago, eight years ago, to work with Phyllis Wise [a physiologist and the first COBRE director], looking at how estrogen protects the brain against stroke injury,” Wilson says. She spent three years as a postdoc and two years as a research associate in Wise’s lab.

Wilson still focuses on estrogen, but today she’s investigating how estrogen may protect the brain from HIV proteins, as well as the role estrogen plays in the cardiovascular system. She ventured into both of these areas because of research relationships fostered by COBRE.

“When HIV gets into the brain, it doesn’t infect neurons directly,” explains Wilson, now an assistant professor in physiology. “It enters the glial cells [cells that surround each neuron and provide protection and nourishment], which then release toxic proteins that can cause neuronal injury and may ultimately lead to HIV-associated dementia.” She adds that with antiretroviral therapy, people live longer than they used to with the disease, but people with long-term HIV infection have a high likelihood of experiencing some sort of cognitive impairment—ranging from subtle memory loss and personality disruptions to severe dementia.

“We know that estrogen plays an important role in protecting the brain and maintaining normal neuronal activity. When postmenopausal women lose estrogen, they become more susceptible to Alzheimer’s and other neurodegenerative diseases. At the moment, there is no strong data that women are more protected against HIV-associated dementia, because clinical data has been limited. This is an emerging field.”

Most of her HIV studies use human cells, and she says, “COBRE funds helped tremendously in outfitting a special, dedicated HIV lab. This is where Annadora Bruce-Keller (who leads the COBRE HIV team), Eric Smart and I can do experiments using live viruses,” Wilson says, adding that such activity is critical. “You have to perform experiments showing that, under conditions of real HIV infection, the things we are testing actually happen in human cells.”

Wilson points out, “I may have never made the connection between estrogen, HIV and cardiovascular research had I not been part of the COBRE. Eric Smart, who leads the COBRE cardiovascular team, had an interest in the gender differences he was seeing in heart disease, so we started collaborating. That work led to my own grant, funded by the National Heart, Lung and Blood Institute, looking at the effects of estrogen on cholesterol accumulation under conditions that induce atherosclerosis—narrowing and hardening of the arteries.

“This collaboration, the start-up funds that gave me my start as a faculty member, and mentoring are all ways I’ve benefited from COBRE. The opportunities for professional development have been very beneficial—and not just from faculty directly over me on paper, but the whole COBRE group,” Wilson says.

Photo ofJane Joseph, Melinda Wilson, Michael Kilgore, and Misung JoCOBRE’s next generation: (from left to right) Jane Joseph (anatomy & neurobiology), Melinda Wilson (physiology), Michael Kilgore (molecular & biomedical pharmacology), and Misung Jo (obstetrics & gynecology). Joseph is tracking brain activation across the menstrual cycle. Wilson is studying the ways in which estrogen protects the brain against HIV and fights cardiovascular disease. Kilgore is exploring how the peroxisome proliferator-activated receptor (PPAR) and the estrogen receptor regulate fertility and reduce breast-cancer risk. Jo is studying the molecular mechanisms involved in ovulation, findings that may lead to better diagnostic tests, more effective contraception and new methods to boost fertility.

Tracking Brain Activation across the Menstrual Cycle
Jane Joseph, who has been part of the COBRE team since 2001 and has grants from the National Institute of Mental Health and the National Science Foundation, is an assistant professor in the anatomy and neurobiology department, but was trained as a psychologist. “My focus was cognition—perception, memory, language,” she explains. “During my postdoc training at Georgetown University, I got into functional magnetic resonance imaging, or fMRI.”

Joseph is using fMRI for an innovative study of women’s cognitive function during a high-estrogen point and a low-estrogen point in their menstrual cycles. And the preliminary results are intriguing.

“fMRI is a lot like getting a routine medical MRI scan—you lay down and your head is in what looks like a cage. Our study participants had a screen in front of their eyes, connected to the cage. We sent images to that screen from a computer in the control room, and the women pushed buttons on a glove-like device so we could record their performance on two tasks.”

The first task tested spatial cognition. Joseph calls it mental rotation, and it’s something most people have seen on a standardized test. “You have a 3-D figure on the left, and you have to pick the one of three other figures that matches it. You have to rotate it in your head,” she explains, then pauses. “I want to be careful how I phrase this, but men tend to complete more of these kinds of tasks and get them correct than do women in a timed version of this test.

“Now, that’s not to say no women do well—it’s just an average gender difference that’s been supported by years of research on pencil-and-paper tests. Some researchers have shown that women do just as well as men if the test is not timed. My thinking is that such a difference is not necessarily bad—women may just be adopting different strategies than men.”

Mental rotation example diagramThis example, from pencil-and-paper tests, shows the mental rotation task. Jane Joseph used a similar task in her brain activation study of nine women.

She explains that the second task tested working memory. “This task involved looking at a sequence of letters, shown one at a time for about 4 seconds each. When each new letter appeared, participants had to decide whether that letter matched the previous letter or the letter shown two time slots before. They also had to keep the current letter in memory because they needed to make this decision each time a letter was presented. I think it’s pretty hard.”

Why test memory? “Sex differences haven’t been studied as much with this type of task, but women on hormone replacement therapy have been shown to perform better on other kinds of memory tests, so we wanted to see if high-estrogen levels correlate with better performance.”

In both of these tasks, Joseph’s goal was to find out what area of the brain was activated and if that changed during the menstrual cycle. “Other studies had produced some evidence that performance varies over the menstrual cycle, but these were subtle differences. So when I got into this, it was pretty controversial stuff.”

The vital part of this study was determining the estrogen levels in her nine study participants. “Tom Curry’s group helped us by doing blood assays to test these levels, and Tom Kelly (who leads the COBRE cognitive function team) was instrumental in guiding the design of this study to capitalize on the high- and low-estrogen phases.” The biggest challenge for Joseph’s team was scheduling women to come in during two different three-to-five day windows during their menstrual cycle.

What did she find? Joseph says these are loose correlations because she didn’t manipulate estrogen levels by having the women take drugs, but her results indicate that on tasks in which men typically out-pace women, like the mental rotation task, brain activation is more extensive when estrogen is low.

Jane Joseph's fMRI brain scansJane Joseph’s fMRI brain scans reveal that for the mental rotation task, brain activation (shown by the dark areas) was more widespread during the low-estrogen phase of the menstrual cycle. The opposite was true for the working memory task—brain activation was more extensive when estrogen was high.

“The opposite occurred for the memory task,” Joseph points out, pulling up a different set of brain scans on her computer screen. “When women had higher estrogen levels, they showed more extensive brain activation doing the memory task than when they had low estrogen.”

What does this mean? Joseph says her results aren’t finalized yet, and, with only nine participants, this was a small sample of women. But Curry says, “This is an intriguing way to tell a story of how hormones affect cognitive behavior. We have to be careful about jumping to conclusions about cognitive processing changing across the menstrual cycle. Should it impact when you take your SAT or GRE? You open Pandora’s box with the possible implications. But these are interesting and relevant questions to study.

“Down the line, these studies and our other basic science projects may lead to important clinical treatments for women,” says Curry. “Leslie Crofford, Sara Jo Nixon, Carol Jordan, Jef Ferguson, and I are all asking, ‘How can we take the things we’re working on and translate them into patient care for people locally and nationally?’ We’re critically interested in moving to the next level—merging basic science and clinical science to make a long-term impact on women’s health.”

Learn more:

Building Interdisciplinary Research Careers in Women’s Health (BIRCWH)
www.mc.uky.edu/bircwh

Center of Biomedical Research Excellence (COBRE) in Women’s Health
www.mc.uky.edu/cobre

Center for Research on Violence Against Women
www.research.uky.edu/crvaw

Center for the Advancement of Women’s Health
www.mc.uky.edu/womenshealth

Kentucky Women’s Health Registry
www.kywomensregistry.com
859-323-5709 or 1-800-929-2320

Mental rotation example diagramVictoria Flanigan (left) was commissioned by Leslie Crofford, director of the Center for the Advancement of Women’s Health, to create a painting for the new Women’s Health Clinic. “She was exploring issues of body and acceptance. I think it’s important that we be conscious of the relationship between women and their bodies,” says Crofford. Flanigan, who created the cover of this magazine and artwork for this article, earned her master’s degree in fine arts at UK in May 2006.

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