Determining if Estrogen is Protective Against Degenerative Changes in Blood Vessel Walls
Aydin Arici, M.D., Professor of Obstetrics and Gynecology
Coronary artery disease (CAD) is a major contributor to making cardiovascular disease the leading cause of death among women. The decline of estrogen in women is associated with increased CAD, yet the underlying mechanisms through which estrogen may be a protective factor against CAD is unknown. Dr. Arici’s study examined whether estrogen has a protective effect against degenerative changes in blood vessel walls by inhibiting a protein that recruits damage to artery walls.
Highlighted Study Findings
One way in which estrogen seems to have a protective effect against degenerative changes in blood vessel walls is by inhibiting a protein that recruits damage to the walls of arteries. Among the earliest recognizable events in atherosclerosis (hardening of the arteries) are a build-up of plaque in the arterial wall and an increased influx of macrophages (which initially serve a disease-fighting positive role). Recent data indicate that a specific protein, known as monocyte chemotactic protein-1 (MCP-1), may act to recruit macrophages to the artery wall in numbers that begin to play an adverse role. Dr. Arici studied the impact of estrogen on MCP-1 using a mouse model. The results of this study suggest that one way in which estrogen seems to have a protective effect against degenerative changes in blood vessel walls is by inhibiting MCP-1. This finding provides specific insights into the mechanisms of estrogen’s action. Better understanding of the selective molecular mechanisms of estrogen’s action is necessary for the development of improved estrogenic substances which preferentially affect certain tissues, such as heart, rather than others, such as breast. These new agents are necessary provide more targeted interventions for women and thus provide a major benefit to their health.
Understanding the Brain's Response to Ovarian Hormones
Ronald S. Duman, Ph.D., Professor of Psychiatry and Pharmacology
Mood disorders such as depression are more prevalent in women than in men, and often precipitated by stress. Studies have suggested that mood disorders may result in part from the effects of stress on the growth and survival of brain cells. Dr. Duman has studied how estrogen may play a role in mood disorders by influencing a major mechanism that sustains brain cells, including those important for mood.
Highlighted Study Findings
In this Ethel F. Donaghue Women’s Health Investigator Program-funded study, Dr. Duman examined the impact of estrogen on the expression of BDNF (Brain-derived neurotrophic factor) - a growth factor that helps support the survival of existing nerve cells, or neurons, and the growth of new nerve cells. His results demonstrated that estrogen influences the expression of BDNF, suggesting a route by which fluctuations of hormones could contribute to neurobiological dysfunction. Moreover, interactions between fluctuating hormones and stress could further compromise the functioning of neurons. These findings represented the beginnings of a foundation for developing strategies to counteract the effects of stress and hormone fluctuations on BDNF expression and neuronal functioning. Continued research and progress in this area will eventually lead to a more complete understanding of the cellular basis of the effects of hormones on mood.
Determining the Effects of Hormone Therapy on Memory
Karyn Frick, Ph.D., Assistant Professor of Psychology
One of the key studies within the NIH-funded Women's Health Initiative suggested that treatment with estrogen and progestin significantly increases the risk of cognitive decline and dementia in postmenopausal women. Those data sharply contrast with studies in women and rodents that have demonstrated a clear ability of estrogen to alleviate age- and hormone-related memory loss. Dr. Frick’s study was designed to determine the effects of estrogen and progesterone on memory.
Highlighted Study Findings
Dr. Frick found in using a mouse model that, to preserve memory, estrogen likely needs to be administered during a critical window – for example, when women are just entering menopause. Such therapy would appear to be of little benefit to women who are well past menopause, and could increase health risks. Building on earlier pilot research, Dr. Frick investigated estrogen relative to a cell-signaling pathway in the hippocampus – an area of the brain critical to learning and memory. Dr. Frick’s lab previously identified this area as crucial to estrogen’s ability to enhance memory. She found that estrogen activated this signaling pathway in the hippocampus and improved the ability of middle-aged female mice to recall objects. However, estrogen had no effect on memory or cell signaling in older female mice. The data support the notion of a window of opportunity early in menopause in which hormone treatment can benefit cognition, and suggest that the failure of estrogen to improve memory in older females may result from dysfunction of specific molecular pathways in the brain.
Pilot Project Study was funded in 2005, Dr. Frick is now at the University of Wisconsin
Urinary Tract Infections
Dr. Toby C. Chai hopes to determine how estrogen provides natural protection to prevent and treat chronic urinary tract infections.
For elderly women, urinary tract infections (UTIs) are not just a nuisance. They can be fatal.
And as antibiotics continue to lose effectiveness from overuse, the need for alternative treatments grows greater than ever.
With the help of the second-ever Wendy U. and Thomas C. Naratil Pioneer Award, Dr. Toby C. Chai, Professor and Vice Chair of Research in Urology, aims to determine if localized, targeted application of estrogen can provide protection to prevent and intervention to treat chronic UTIs.
“We’re running out of antibiotics,” Chai said. “We utilize them so frequently the bacteria have become smart. They develop resistance quickly. We really have to open up new avenues to be able to find new treatments for infections.”
One out of two women experience UTIs in their lifetimes, and UTIs recur 25 percent of the time even after appropriate antibiotic treatment as they develop resistance. Recently, only a few new antibiotics have been approved for treating UTIs.
A recent survey revealed 4.2 million emergency room visits for UTIs, with the largest number among women between the ages of 45 and 54, suggesting the depletion of estrogen in menopause as a possible factor for the increased incidence. In fact, although there are no clinical trials that have tested the efficacy of estrogen for UTIs, it is often used to treat these infections in clinical practice despite some patients’ fears of adverse effects.
Chai’s team will study mice genetically altered to produce increased estrogen activity in the bladder lining to see how they resist bladder infections. Chai then hopes to identify other natural mechanisms triggered by estrogen’s activity, possibly leading to treatments other than estrogen or traditional antibiotics that can save lives.
“It’s research like this that aims to deliver on the long-delayed promise of science to offer answers appropriate to real-life clinical problems,” Mazure said. “If successful, Dr. Chai will revolutionize treatment of recurrent UTIs that are both burdensome and deadly.”
About the Investigator
Dr. Toby C. Chai earned his M.D. from the Indiana University School of Medicine and his B.A. from John’s Hopkins University. Since 2013 he has served as a Professor and Vice Chair of Research for the Yale School of Medicine’s Department of Urology.
For the last 15 years, his research has focused on the behavior of urinary tract tissue and cell communication in non-cancerous bladder conditions.
The Wendy U. and Thomas C. Naratil Pioneer Award, supported by an endowment gift from a Yale College ’83 couple, expands our Pilot Project Program by funding investigations that are highly inventive or close to a major breakthrough in advancing women’s health.