Women are more than twice as likely as men to develop stress-related conditions such as posttraumatic stress disorder (PTSD), but the biological reasons for this increased risk have not been well understood. New research from Emory University School of Medicine provides direct evidence in humans that the ovarian hormone estradiol is a key factor in how the brain responds to perceived threats after trauma.
The study, published on December 15 in the Proceedings of the National Academy of Sciences (PNAS), was supported by the National Institutes of Health and the National Science Foundation. Researchers found that estradiol affects activity in brain regions related to threat detection, and traumatic stress can disrupt this effect.
“Our findings suggest that ovarian hormones have an important influence on the brain’s threat-detection circuitry, but traumatic stress appears to interfere with these normal regulatory processes,” said Jennifer S. Stevens, PhD, associate professor in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine and principal investigator of the study.
The research team studied 110 women enrolled in the Grady Trauma Project, an Emory-led initiative focused on understanding psychological and biological effects of trauma. Participants included women with PTSD, women exposed to significant trauma without developing PTSD, and women with little or no lifetime trauma.
Participants were randomly assigned to receive either a skin patch delivering estradiol or a placebo during phases of their menstrual cycle when natural estradiol levels are low. After 24 hours, they underwent functional MRI scans while viewing images designed to measure brain activity related to social threat cues.
Results showed that among women with PTSD who received a placebo, naturally low estradiol levels were linked to increased activity in the central amygdala—a region involved in fear expression and physiological stress responses. For women with little or no trauma exposure, receiving estradiol during certain menstrual phases reduced activity in both the central amygdala and a nearby region called the corticomedial amygdala.
However, for women who had experienced significant trauma but did not have PTSD, estradiol increased activity in both amygdala regions. In contrast, among women with PTSD, estradiol had no measurable effect on these areas. The findings indicate that trauma exposure may change how the brain responds to estradiol and disrupt its typical role in regulating reactions to perceived threats.
Researchers used high-resolution functional MRI to pinpoint these effects within specific subregions of the right amygdala known for having many estrogen receptors and playing a central role in fear-related behavior.
This work builds on previous studies from Emory researchers showing that low estradiol levels after ovulation can strengthen negative memory encoding by changing activity in another part of the brain called the entorhinal cortex. These results suggest that hormonal changes following ovulation may be especially important for understanding how PTSD develops or persists.
“This work helps address a major gap by identifying biological processes that may contribute to women’s risk and highlights the need to consider how trauma and hormones interact when thinking about prevention, screening and treatment,” explained Stevens.
The PNAS study included multiple Emory researchers: co-investigators from both the Grady Trauma Project and psychiatry department—Vasiliki Michopoulos, Abigail Powers Lott, Sanne van Rooij—as well as Kim Wallen (psychology), Andrea Braden and Marisa Young (gynecology/obstetrics), and Kelly Ethun (pathology/laboratory medicine).
