Women are more than twice as likely as men to develop stress-related conditions such as posttraumatic stress disorder (PTSD), but the biological mechanisms underlying that risk have remained poorly understood. New research from Emory University School of Medicine provides the first direct evidence in humans that the ovarian hormone estradiol plays a key role in shaping how the brain responds to perceived threats after trauma.
The study, published Dec. 15 in the Proceedings of the National Academy of Sciences (PNAS), was supported by the National Institutes of Health and the National Science Foundation. It shows estradiol influences activity in threat-related brain regions and traumatic stress can disrupt this regulatory 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,” says 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.
Stevens and her colleagues studied 110 women enrolled in the Grady Trauma Project, a long-running Emory-led research initiative that examines the psychological and biological effects of trauma. Participants included women with PTSD, women with significant trauma exposure but no PTSD and women with little to no lifetime trauma.
Participants were randomly assigned to receive either a skin patch delivering estradiol, the primary ovarian estrogen, or a placebo. Patches were administered during either the luteal or follicular phases of the menstrual cycle, periods when estradiol levels are naturally low. Twenty-four hours later, participants underwent functional MRI scans while viewing images of fearful and neutral faces, allowing researchers to measure activity in brain regions involved in processing social threat cues.
Among women with PTSD who received the placebo, naturally low estradiol levels were associated with heightened activity in the central amygdala, a brain region critical for fear expression and physiological stress responses. In contrast, among women with little to no trauma exposure, estradiol administered during the luteal phase reduced activity in the central amygdala and a nearby region called the corticomedial amygdala.
The pattern differed among women with trauma exposure. For women who experienced significant trauma but did not meet criteria for PTSD, estradiol increased activity in both amygdala regions. Among women with PTSD, estradiol had no measurable effect on either region. These findings suggest trauma exposure may alter how the brain responds to estradiol and interfere with its normal role in regulating responses to perceived threats.
Using high-resolution functional MRI, the researchers identified these effects within specific subregions of the right amygdala that are densely populated with estrogen receptors and play a central role in fear-related physiology and behavior.
The findings build on another recent study from the same research team showing low estradiol levels after ovulation strengthen the brain’s encoding of negative memories by altering activity in the entorhinal cortex, a region that serves as a gateway to the hippocampus. Together, the studies suggest the post-ovulation period may be a particularly important window when hormonal fluctuations influence PTSD-related brain processes.
“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,” explains Stevens.
The PNAS study involved multiple Emory researchers, including study co-investigators from the Grady Trauma Project and the department of psychiatry and behavioral sciences: Vasiliki Michopoulos, Abigail Powers Lott and Sanne van Rooij. Additional investigators included Kim Wallen (psychology), Andrea Braden and Marisa Young (gynecology and obstetrics) and Kelly Ethun (pathology and laboratory medicine).