Advancements in Women’s Health Research

For more than 25 years, innovative research on health conditions specifically affecting women, more prevalent in women, or affecting women differently than men has been at the core of Women’s Health Research at Yale. The purpose of this focus is to generate needed data on women’s health and discover clinically meaningful information on differences between and among women and men that can advance health and improve lives.

A key mechanism in accomplishing this goal is Women’s Health Research at Yale’s Pilot Project Program. Initiated by Director Carolyn M. Mazure, PhD, at the launch of the center in 1998, this program provides seed funding for pilot studies designed to uncover findings that inform diagnosis, treatment, and prevention of disorders on topics ranging from cardiovascular disease to cancers, Alzheimer’s disease to addiction, and more.

The investment made in these pilot projects has resulted in both valuable health information and the necessary feasibility data for our investigators to apply for external grants. Using the pilot data obtained with our funding, the return on Women’s Health Research at Yale’s investment in the form of external grant dollars is more than 20-fold, and new funds go directly into our investigators’ laboratories and research settings so they can continue the essential work they have begun at Yale.

Women’s Health Research at Yale’s Pilot Project Program has been recognized as a national model for spurring new research on the health of women and uncovering sex and gender differences that affect health outcomes.

So, let’s take a look back at just 10 of the many innovative projects over the course of our history.

Can A Gene Mutation Predict Breast Cancer Recurrence?

Bruce Haffty, MD, is a radiation oncologist and breast-cancer researcher whose work changed how women and their doctors approach the assessment of risk for recurrent breast cancer.

As one of Women’s Health Research at Yale’s first funded pilot projects in 1998, Haffty’s study showed that patients with mutations in the BRCA1 and BRCA2 genes, even after they had been diagnosed and undergone treatment for breast cancer, remained at greater risk for breast cancer recurrence than women without these mutations, which was again proven 15 years later.

This landmark discovery, which was published in The Lancet, provided information that women and their physicians needed to make more informed health decisions regarding both current treatment and cancer prevention. Furthermore, Haffty’s ongoing cancer research has paved the way for new methods of radiation therapy that use molecular and genetic data to determine treatments that reduce radiation resistance and improve outcomes in breast cancer patients.

Can Sex Influence Recovery Following Coronary Bypass?

Also among the inaugural Women’s Health Research at Yale pilot projects was a study by Viola Vaccarino, MD, PhD. A cardiologist and epidemiologist, Vaccarino examined whether there were sex differences in outcomes of coronary bypass surgery. At that time in the U.S., more than 180,000 women per year were having this procedure, yet data were lacking on outcomes for women.

In asking the question, “Do women benefit from the surgery in the same ways men do?,” Vaccarino was first to alert the medical community that women, in fact, had worse outcomes than men after the procedure. In the six to eight weeks after surgery, the most likely time for complications, women were nearly twice as likely as men to be readmitted to the hospital, develop infections, report lower physical functioning, and experience more depressive symptoms. Her study found the difference in outcomes could not be attributed to pre-surgery health status, current illness, or a variety of patient characteristics.

“We found that at six months after surgery, both women and men showed improvement in their functional status, but women had about half the improvement compared to men,” said Vaccarino. This foundational study informed clinicians and researchers for the first time of the increased risk of this procedure for women. Subsequently, we have seen the introduction of robotic surgery on female patients due to smaller arteries, as well as an increase in statin prescriptions to reduce cholesterol and minimize cardiovascular disease. This innovative study showed early on the need to consider sex differences when it comes to the heart.

Can The Right Message Change Behavior?

In a 1999 Women’s Health Research at Yale pilot project, psychologist Peter Salovey, PhD, began focusing on the types of public

service health messages that were effective in encouraging women to increase health promoting behaviors.

At this time, public service announcements focused on techniques meant to frighten a viewer or listener about the outcomes of risk behaviors. Specifically, to harness the greatest power of persuasion, Salovey wanted to determine if the “frame” of a message, whether it communicated a positive or negative outcome, was more likely to reduce risk behavior and influence health promoting behavior.

In Salovey’s initial work, directed toward increasing the use of routine mammography screening in women at elevated risk for breast cancer, he found that for health messages to be effective they must be tailored to how an individual was most open to receiving information. What he found was that for some women, hearing the positive benefits of screening was more likely to promote obtaining a mammogram while for others, hearing potential negative outcomes to ignoring the risk associated with not having a mammogram was more influential.

Salovey then went on to employ these findings, using concepts drawn from social psychology, to develop patient-specific

messaging that resulted in increased rates of health protective behaviors. This work included maximizing the power of messaging to persuade people to change risk behaviors related to sun exposure, tobacco use, and HIV/AIDS.

“As an early awardee of one of Women’s Health Research at Yale’s pilot grants, I was able to develop and test public health messages that encourage women at elevated risk for breast cancer to use routine mammography screening. This work led to a longer-term program of research funded by the National Cancer Institute. Thank you for ensuring that Yale is at the forefront of understanding how gender and sex influence health and illness and for educating health professionals and members of the community,” said Salovey.

Can an MRI Uncover Sex Differences of a Mood Disorder?

In her 2002 pilot project, psychiatrist Hilary Blumberg, MD, examined sex differences in the brain as it relates to bipolar disorder, a mood disorder affecting approximately 7 million Americans. Although the rates of bipolar disorder are the same for women and men, there are aspects of the disease that are different by sex and lead to worse outcomes. For example, women are more apt to suffer from depression, which increases suicide risk.

By comparing MRI brain scans of adolescent females and adolescent males, Blumberg and her team made important discoveries that revealed sex-specific differences in the brain that resulted from exposure to childhood maltreatment, including physical and emotional abuse and neglect. This research showed why females may be more likely than males to develop depression if they have suffered maltreatment. Further research by her group showed how early stress exposure could lead to differences in brain development, providing information about sex differences in pathways to the high rates of substance abuse and suicide in persons with bipolar disorder.

More than 20 years later, Blumberg continues to explore bipolar disorder as director of Yale’s Mood Disorders Research Program.

Can Antibodies Be Used As Cancer Treatments?

As a professor of both therapeutic radiology and genetics, Peter Glazer, MD, PhD, investigates new therapeutic strategies for treating cancer and the role of altered DNA repair in tumor progression. DNA repair is a collection of processes where a cell identifies and corrects damage to the DNA molecules that maintains integrity of the cell.

Based on a discovery from his laboratory showing that a lupus antibody, known as 3E10, can penetrate cancer cells and make them more vulnerable to radiation therapy and chemotherapy, Glazer applied for Women’s Health Research at Yale funding in 2012 to begin the process of uncovering the biological basis for how this occurs – the first step necessary in using this finding to a develop a treatment intervention.

The basic work of this grant began a process that successfully led to identifying the biological underpinnings of this finding. Glazer now has been able to design a drug intervention to potentially treat cancers, such as ovarian and breast cancer, that develop from inherited mutations to the BRCA2 gene, which suppresses tumor development. Currently, his novel process of using this antibody as a cancer therapy is being investigated in clinical trials.

“This discovery has unlocked promising new pathways for treatment of BRCA-related cancers that affect so many women around the world,” said Glazer.

Can Girls Benefit From An Autism Treatment Developed for Boys?

For years, rates of what was known as autism were higher for boys than girls, however, as clinicians and researchers increasingly

understood autism as a spectrum disorder, more girls were diagnosed along this spectrum.

As an active clinician, Pamela Ventola, PhD, saw the value of social-behavioral interventions in the treatment of autism spectrum disorder. However, an effective such therapy, Pivotal Response Therapy (PRT), had been developed and tested with boys, and there were no data on the efficacy of PRT for girls with autism spectrum disorder.

In a Women’s Health Research at Yale funded pilot project in 2015, Ventola showed, for the first time, that PRT helped girls as well as boys, and that the net benefit was greater in girls than boys.

In addition, these results led to team-based research that was successful in identifying a brain signal – detected by a non-invasive brain scan – that predicted which girls and boys were most likely to respond to PRT. Finding a pretreatment predictor of a good response was especially valuable because PRT is an intensive 16-week intervention requiring direct clinician intervention plus parental guidance. Moreover, early childhood is a window of opportunity for effective treatment that reduces the long-term personal cost for child and family.

Can Studying Single Cells Reveal Sex Differences in Alzheimer’s Disease?

The human brain contains about 100 billion individual cells that form a variety of cellular structures in the tightly packed, interconnected landscape of the human brain. For researchers seeking precise causes of impairment from Alzheimer’s disease and other dementias, the brain’s intricacy and diversity in the molecular underpinnings of these diseases have made it difficult to devise prevention strategies and treatments.

“We know so little about how Alzheimer’s disease develops,” said Le Zhang, PhD, a faculty member in charge of single-cell experimental design and data analysis at Yale School of Medicine’s Department of Neurology. “In order to understand what is happening to people with such a complex disease, we need to start at the cellular level. That must include looking at sex-specific differences that exist in single cells of women and men.”

In a major step toward this crucial understanding, Women’s Health Research at Yale co-funded a pilot project with the Yale Alzheimer’s Disease Research Center in 2020 for Zhang and neuroscientist Stephen Strittmatter, MD, PhD, to uncover sex-specific differences in the origins of Alzheimer’s disease by studying single cells.

“By understanding the subtle differences among cell populations in Alzheimer’s disease, we can build upon our knowledge of abnormalities that cause cell death and how they relate to disease symptoms such as cognitive dysfunction,” said Strittmatter. “Such knowledge has the potential to identify hidden biological clues and produce novel therapeutic targets that will benefit women and men suffering from or at risk for developing this destructive disease.”

And their pilot project proved successful: the investigators found subtle differences among cell populations gathered from women and men with and without Alzheimer’s disease. This uncovered biological information about what may cause pathological changes in brain cells. Soon after, Women’s Health Research at Yale connected Zhang and Strittmatter with another funded investigator, Hongyu Zhao, PhD. They formed a collaboration that resulted in a significant grant from the National Institutes of Health to continue their research.

Can A Mindfulness-Based Intervention For Insomnia Help Black Women?

With a pilot grant from Women’s Health Research at Yale in 2021, Soohyun Nam, PhD, tested — for the first time — an evidence-based stress-reduction intervention for insomnia that has shown potential for addressing the underlying causes of sleep difficulty in a manner culturally sensitive to the needs of Black women. Nam’s approach used a mindfulness-based therapy for insomnia (MBTI), that provides an eight-week group therapy program through which participants gain an awareness of the thoughts that fuel stress. In addition, they learn the skills to regulate their response to stress. The program included daily home practice and was designed to cultivate non-judgement, self-compassion, and present-focused awareness.

Nam and her team compared the amount and quality of sleep in participants who were randomly assigned to either the MBTI group or a control group of participants who received general education in healthy eating, physical activity, and proper sleeping strategies. She found the group receiving the MBTI intervention had improved sleeping and reduced levels of stress compared with the control group. With these data in hand, she designed a much larger trial to justify the widespread dissemination of this intervention for the benefit of this underserved population of women. As a result, Nam received two grants for more than $2.5 million to continue her research.

“Mindfulness focuses on how you live with the stress, not just how you get rid of it,” Nam said. “You regulate your emotion. And hopefully, we can help women achieve the rest they need so they can better maintain their health and well-being.”

Can Women With Chest Pain Benefit From Precision Diagnostics?

A heart attack occurs when the flow of blood to the heart is severely reduced or blocked, most often in a major cardiac artery. The current standard method for diagnosing a heart attack is a coronary angiography – a procedure in which a long, thin tube is inserted through the blood vessels to the heart, contrast dye is injected, and X-rays are used to look for the blockages caused by cholesterol build-up, called plaque.

In his 2021 Women’s Health Research at Yale pilot study, Samit Shah, MD, tested a new diagnostic approach that he developed for detecting reduced blood flow to the heart in patients who have symptoms of heart disease without blockages, which occurs more commonly in women. In fact, about 50 percent of women who suffer from heart disease do not have significant coronary artery disease with plaque buildup. After determining the lack of a coronary blockage, Dr. Shah focuses on detection of microvascular or “small vessel” disease and coronary vasospasm using specialized cutting-edge diagnostic tools. These include the use of a wire that measures 0.014 inch, which can assess pressure and flow, as well as routine testing with a medication called acetylcholine, which tests the ability of blood vessels to open, or dilate, to increase blood flow. These conditions cannot be diagnosed with routine coronary angiography and without these tests, patients are left without a clear diagnosis.

Shah has now studied more than 175 women over two years at Yale New Haven Hospital, comparing the outcomes for patients who underwent coronary angiography, the historical standard of care, with those who undergo advanced testing for microvascular disease or coronary vasospasm during the same procedure. Using this method, more than 80 percent of women have been given an accurate diagnosis and treatment plan, which has been shown to lead to better symptom relief and quality of life.

In June 2024, Shah’s groundbreaking work was published in JSCAI, the official journal of the Society for Cardiovascular Angiography & Interventions, in an article titled, “Evaluating Ischemic Heart Disease in Women: Focus on Angina With Nonobstructive Coronary Arteries.”

Can A Baby’s Outcomes Be Improved With Nanoparticles?

One of the leading causes of premature delivery during pregnancy is intra-amniotic infection (IAI). This occurs when bacteria

infect the placenta, the amniotic fluid, and the membranes that line the uterus and maintain the structure of the amniotic sac. The bacteria are protected by a gel-like barrier called biofilm, making the infection even more difficult to treat with antibiotics. Without a treatment, delivery must occur quickly once IAI has been identified, which puts infants at risk of both short and long-term health challenges.

In his 2023 Women’s Health Research at Yale pilot project, pediatric surgeon and researcher David Stitelman, MD, and his team are studying whether biodegradable synthetic particles called nanoparticles – invisible to the naked eye and about 1/100^th the size of a single speck of dust – can pass through the biofilm and deliver the antibiotics to directly combat the bacteria.

“With the use of nanoparticles, we expect to see the infection clear within hours. The particles can be designed to release a large dose of antibiotics immediately and then continue to slowly release medication over days or weeks to maintain the sterile environment. Even a few more weeks of gestation dramatically improve outcomes for premature infants,” Stitelman reflects.

If the research team is successful at tailoring nanoparticles to deliver antibiotics for treatment of the IAI, they will be well positioned to continue trials on the path to a new treatment that will improve the health of newborns and women alike.

Innovation Abounds

“For more than 25 years, innovative investigators at Yale have made excellent use of our pilot project funding to understand and improve the health of women. They have made valuable inroads into understanding human biology and social factors that determine the health of women,” said Mazure, the Norma Weinberg Spungen and Joan Lebson Bildner Professor in Women’s Health Research and professor of psychiatry and psychology. “These projects have built a foundation that allows us to move forward in improving the health and lives of women and men.”

This is just a snapshot of projects that have made differences in their respective fields and in medicine more generally. Together, Women’s Health Research at Yale Investigators account for more than $115 million in external grants, bringing essential funding back to Yale University and continuing the cycle of innovation.

About Our Investigators: Current Positions

• Hilary Blumberg, MD, John and Hope Furth Professor of Psychiatric Neuroscience and Professor of Psychiatry, Radiology, and Biomedical Imaging, and in the Child Study Center; Director, Mood Disorders Research Program; Yale School of Medicine

• Peter Glazer, MD, PhD, Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Therapeutic Radiology, Yale School of Medicine

• Bruce Haffty, MD, Chair, Radiation Oncology, Associate Vice Chair for Cancer Programs, Rutgers Cancer Institute, Rutgers University

• Soohyun Nam, PhD, Associate Professor with Tenure, Yale School of Nursing; Affiliated Faculty, Yale Institute for Global Health, Yale School of Medicine

• Peter Salovey, PhD, Chris Argyris Professor of Psychology; Professor, Chronic Disease Epidemiology, Yale University; 23^rd President of Yale University

• Samit Shah, MD, PhD, Assistant Professor of Medicine, Yale School of Medicine; Director, VA Connecticut Cardiac Catheterization Laboratory

• David Stitelman, MD, Associate Professor of Pediatric Surgery, Yale School of Medicine

• Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology and Professor of Neuroscience; Chair, Neuroscience; Director, Kavli Institute for Neuroscience; Director, Cellular Neuroscience, Neurodegeneration and Repair; Director, Memory Disorders Clinic; Director, Yale Alzheimer’s Disease Research Center, Yale School of Medicine

• Viola Vaccarino, MD, PhD, Rollins Professor and Chair, Department of Epidemiology, Rollins School of Public Health, Emory University

• Pamela Ventola, PhD, Associate Professor, Child Study Center, Yale School of Medicine

• Le Zhang, PhD, Assistant Professor of Neurology and Neuroscience, Yale School of Medicine

• Hongyu Zhao, PhD, Ira V. Hiscock Professor of Biostatistics; Professor of Genetics and Professor of Statistics and Data Science, Yale School of Public Health