Can immune responses known to be sex-specific affect the outcome of stroke and provide a basis for improved interventions?
Can lowering insulin levels help women avoid an overgrowth of abnormal cells in the uterine lining that leads to cancer? And teach us more about how cells become cancerous?
Can a steroidal medication reduce pain and thus the need for narcotics in women recovering from past opioid use undergoing childbirth through a cesarean section?
Can studying single cells reveal sex-specific causes of Alzheimer’s disease to help women and men avoid or slow the disease’s progression?
At WHRY, we are focusing our research efforts on women in the time of the COVID-19 pandemic. At the same time, we are accelerating our work to address the enduring and pressing medical conditions that continue to affect women’s lives. These four new studies will advance our understanding of and capacity to reduce disease and death caused by cardiovascular disease, cancer, and addiction.
Exploring Sex Differences in Immune Response to Stroke
There have been recent advances in the study of sex differences. This research has shown distinct differences in the way brain tissue responds in women and men after acute brain injuries. But researchers know little about sex-specific cellular responses in the brain following a devastating type of stroke. This type of stroke is called an intracerebral hemorrhage. Lack of knowledge limits the ability of researchers to develop effective therapies that account for these differences.
Every year in the United States, 40,000 to 67,000 people experience intracerebral hemorrhage. This happens when the rupture of a penetrating artery within the brain leads to bleeding inside brain tissue. This mass of blood within the brain sets off an immune response. This response includes activation of white blood cells called brain macrophages. The hemorrhage also attracts other white blood cells to the brain. This initial response leads to more collateral damage that kills brain cells and harms the bodily functions they control.
There is currently no effective, targeted treatment for this condition. And an average of between 35 to 52 percent people with intracerebral hemorrhage die within 30 days. After six months, only 20 percent of survivors are able to live without help.
Dr. Sansing is using a technique known as single-cell RNA sequencing (scRNAseq) analysis. This technique isolates individual cells to produce genetic data. This data shows how different cell types function in response to this specific form of stroke. The method captures differences in cell states across thousands of key types of immune cells in the brain in a single set of experiments.
Dr. Sansing wants to learn how each single cell responds to this type of brain injury. This can inform us about the types of immune cells responsible for injury and those that help in repair and recovery. Of great medical interest, this research provides us with data on which type of immune cell does what, and when, and how this is different for women and men.
Dr. Sansing wants to determine if her animal model will show that older females have a distinct cellular response after this type of stroke. This could include enhanced recruitment of different types of immune cells than males. Such knowledge would inform different treatment approaches for females and males.
“The molecular pathways of damage and recovery after intracerebral hemorrhage represent robust targets for therapeutic intervention,” Sansing said. “We know some immune responses are different for women and men, but the vast majority of laboratory studies utilize young males. Our new study will allow for global and in-depth analyses of differences across sexes and ages that can lead to investigation of effective therapies for women and men.”
Investigating Lowering Insulin Levels to Prevent Endometrial Cancer
In the United states, experts estimate that by the end of 2020 about 65,000 women will develop cancer of the uterus. This includes the uterine lining known as the endometrium. A total of about 12,000 women will die of the disease.
Diagnoses of endometrial cancer are growing fastest among premenopausal women. In particular, the disease is twice as common in overweight women as in women of a healthy weight. And it is more than three times as common in obese women.
Atypical endometrial hyperplasia (AEH) is an overgrowth of abnormal cells in the uterine lining. AEH develops into endometrial cancer in about 30 percent of cases. This provides a unique window into cancer development and an opportunity for preventative therapy. Current treatments include removing the uterus through hysterectomy. This ends a woman’s capacity for reproduction. Another treatment involves blocking estrogen action in the endometrium through administration of progestin. Progestin is a synthetic hormone like naturally occurring progesterone. Importantly, this latter treatment has a low success rate in preventing cancer.
In pursuit of better outcomes, Dr. Clare Flannery, Associate Professor of Endocrinology and of Obstetrics, Gynecology, and Reproductive Sciences, is determining which obesity-induced changes in the endometrium will lead to the atypical endometrial tissue (hyperplasia) that leads to cancer. Of particular interest are higher insulin levels. This is a feature of obesity in premenopausal women that can also contribute to irregular menstrual cycles. Irregular menstrual cycles expose the uterus to chronically excessive levels of the hormone estradiol without the protective effect of progesterone.
Dr. Flannery is examining how lowering insulin levels can help women avoid AEH that leads to endometrial cancer.
“Therapy for atypical endometrial hyperplasia has remained unchanged for several decades and is inadequate for the increasing number of women who will need it,” Flannery said. “Our work is attempting to change the paradigm of endometrial cancer development, allowing additional therapies to be used in its prevention.”
Dr. Flannery is examining the effect of high levels of insulin and estradiol treatment in an animal model. She will compare the findings to archived samples of AEH and normal endometrium tissue from women. She expects to find specific ways in which insulin disrupts cell physiology toward AEH, particularly in the presence of estradiol.
“Since many medications will lower insulin and have few side effects, their use is only limited by the lack of data to support a therapeutic rationale,” Flannery said. “This pilot study, once completed, can serve as data to initiate a large-scale clinical trial of insulin-lowering medications in women with AEH for whom progestin therapies have failed.”
Testing an Alternative to Opioids in Cesarean Section
Over the last 20 years, more than 200,000 Americans have died from prescription opioid overdoses. Women are particularly vulnerable to this epidemic because of differences in pain sensitivity compared to men. And women are more likely than men to begin their use of opioids through prescription misuse. Women are also more likely to be prescribed opioids with other medications. This further increases the likelihood of an overdose. From 2008 to 2012, one in three women of reproductive age filled a prescription for an opioid medication.
The most recent data suggest between 14 and 22 percent of women have filled an opioid prescription during pregnancy. Between 1999 and 2014, opioid use rates during pregnancy increased by 400 percent.
Two recent statewide studies in Utah and Colorado found that postpartum opioid-related overdose was the leading cause of maternal mortality. The researchers attributed this to various uses of opioids to control pain. Such as postoperative pain after a cesarean section delivery. Pain is an especially worrisome factor for patients with opioid use disorder (OUD). These patients have developed a tolerance to opioids. This requires higher doses to achieve adequate pain control.
Currently, obstetricians use medication assisted treatment (MAT) for pregnant patients with OUD. They prescribe drugs such as methadone or buprenorphine to optimize health outcomes before and after birth. But relapse risk for women with OUD increases in the postpartum period, even with MAT. And with relapse comes repeated cycles of withdrawal and increased risks of infectious diseases, overdose, and death.
Current guidelines encourage alternates to opioids for pain management in pregnant patients with OUD. But there have been no studies of such patients to guide these strategies.
“Women with opioid use disorder on medication assisted treatment are more likely to experience higher pain levels and require higher opioid doses after cesarean section deliveries than women without an opioid use disorder,” Merriam said. “If proven effective, our intervention to target postoperative pain in this high-risk group would help to reduce opioid use after delivery and lower the risk of relapse.”
Dr. Merriam will test if the steroid dexamethasone reduces pain among 40 patients undergoing a cesarean section. The study design includes an experimental group receiving the steroid. A control group is receiving a placebo. The researchers are evaluating the patients’ postpartum scores on a series of pain questionnaires. They are also monitoring the amount of opioids they need. Dr. Merriam anticipates that women receiving the dexamethasone treatment will have lower average pain scores. She also is testing to see if they need a lower average dose of narcotics during the postpartum inpatient stay.
“This study offers a promising method to decrease pain and narcotic use in patients with a past history of opioid use,” Merriam said. “And because of Yale New Haven Hospital’s diverse patient population, we believe our results could also apply to populations of women throughout the United States.”
Studying Alzheimer’s Disease Inside Single Cells
Alzheimer’s disease (AD) is the most common neurodegenerative disease, and there is currently no effective treatment. Symptoms include progressive memory loss and cognitive dysfunction, with significant impact on daily functioning for those struggling with the disease and on the lives of their caregivers.
More than 5.5 million people in the United States have Alzheimer’s disease, two-thirds of whom are women. In addition, women have a much higher risk for developing the disease, attributable to more than an average life expectancy longer than men. One in five women ages 65 and older are at risk, compared to one in 11 men. Women with AD also have more severe cognitive symptoms and neurodegeneration.
What has made Alzheimer’s disease especially difficult to treat is that it involves many types of cells, including neurons, cells that insulate neurons called glial cells, and disease-fighting immune cells. Not only do malfunctions in each of these cell types contribute to the disease on their own, these cell types also interact with each other, further complicating our understanding of disease development.
It is also currently unclear how the cellular mechanisms underlying Alzheimer’s disease contribute differently to symptoms in women and men. Thus, a precise understanding of how single cells of varying types function in healthy and disease states in women and men has the potential to open doors for sex-specific treatment of AD.
Recently, researchers have developed ways to analyze subtle differences among individual cells, producing huge amounts of genetic data that can reveal important insights into cell types and diseases. The techniques, collectively called single-cell analysis, offer a unique opportunity to discover potentially different origins of disease in women and men.
The researchers are building upon their previous work to discover how subpopulations of neuronal, glial, and immune cell types contribute differently to Alzheimer’s disease based on sex.
“There must be a reason why Alzheimer’s disease is more severe in women and why women are at such greater risk,” Zhang said. “What is happening on a cellular level? What are the different molecular pathways leading to disease? These are the types of questions we are asking and answering.”
By studying the individual brain cells of subjects with and without Alzheimer’s disease, the researchers will be able to identify sex-specific cell populations and signaling pathways altered during the development of AD. These results will form the basis for future studies to target these cells and try to help women and men avoid or slow the disease’s progression.
Women's Health Research at Yale's Pilot Project Program
The Pilot Project Program is made possible by The Rice Family Foundation, The Werth Family Foundation, the Community Foundation for Greater New Haven, and the Maximilian E. and Marion O. Hoffman Foundation.
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