For decades, scientists have known that estrogen protects cardiovascular health, but exactly how that protection works—and what happens when it disappears—has remained unclear. New research from University of Texas at Arlington points to the liver and the immune system as critical players.
The research team, led by Subhrangsu S. Mandal, professor of chemistry and biochemistry, and Linda Perrotti, professor of psychology, found that estrogen plays a powerful role in regulating liver health, inflammation control and energy processing in the body. When estrogen levels decline, these systems become disrupted, contributing to changes linked to heart disease risk after menopause.
Restoring estrogen reversed many of these effects, suggesting that hormone linked immune and metabolic pathways may be important targets for preventing heart disease in women after menopause. The findings deepen understanding of how estrogen deficiency leads to liver inflammation and unhealthy changes in cholesterol levels, an advancement in women's health that could lead to new treatments for cardiovascular disease in women after menopause.
Women face a substantially lower risk of heart disease than men before menopause, but that risk rises sharply afterward, even without major lifestyle changes.
"Estrogen and cholesterol have been a long standing interest in my lab. It's well known that estrogen controls plasma lipid and cholesterol levels, and when estrogen declines, cholesterol levels increase, which raises the risk of heart disease," said Dr. Mandal, whose work was published in Scientific Reports. "What we're trying to understand is how estrogen loss sets off that chain reaction."
Beyond postmenopausal symptoms, hormonal imbalance is also linked to a wide range of health conditions, including polycystic ovary syndrome (PCOS), endometriosis, osteoporosis, nonalcoholic fatty liver disease, weight gain, infertility and several autoimmune disorders.
A key finding from the study involved an enzyme related to inflammation called indoleamine 2, 3-dioxygenase-1, or IDO1, already known as a target in cancer immunotherapy. Under inflammatory conditions, this enzyme changes how immune cells handle nutrients and cholesterol.
"When IDO1 is activated, immune cells lose their ability to remove cholesterol efficiently," Mandal said. "In this study, we found that estrogen deficiency increases IDO1 levels in the liver, linking hormone loss to metabolic and heart disease risk."
The impact was not confined to the liver. Blood markers showed signs of widespread inflammation, suggesting a whole-body stress response.
"This tells us estrogen loss doesn't just affect one organ," Mandal said. "It creates a systemwide inflammatory state that interferes with metabolism and increases disease risk."
While estrogen replacement can reverse many of the observed changes, Mandal cautioned against viewing hormone therapy as a simple solution.
"Hormone therapy can improve cardiovascular and liver function, but it also increases the risk of breast and ovarian cancers," he said. "That's why we need alternatives."
The findings point toward new possibilities, including targeting inflammatory and metabolic pathways —like IDO1—without directly replacing hormones.
"If we could develop a safe, pill-based drug—something more like a Tylenol than an antibody therapy widely used for immunotherapies—it could be transformative," Mandal said.
UTA graduate students Prarthana Guha, Ascharya Rishi and Avisankar Chini were first authors on the project.
About The University of Texas at Arlington (UTA)
The University of Texas at Arlington is a growing public research university in the heart of Dallas-Fort Worth. With a student body of over 42,700, UTA is the second-largest institution in the University of Texas System, offering more than 180 undergraduate and graduate degree programs. Recognized as a Carnegie R-1 university, UTA stands among the nation's top 5% of institutions for research activity. UTA and its 280,000 alumni generate an annual economic impact of $28.8 billion for the state. The University has received the Innovation and Economic Prosperity designation from the Association of Public and Land Grant Universities and has earned recognition for its focus on student access and success, considered key drivers to economic growth and social progress for North Texas and beyond.
