New research published in Brain Imaging and Behavior suggests that estradiol, a primary form of estrogen, influences how different areas of the brain communicate during memory tasks in middle-aged women. The findings provide evidence that higher levels of this hormone tend to allow for more efficient brain connectivity when recalling information. This research offers insights into how hormonal shifts might shape cognitive changes during the transition to menopause.
Midlife in women involves a major hormonal transition known as perimenopause, which leads up to menopause. During this period, the body experiences dropping levels of estradiol, which is the most potent and abundant form of estrogen in the human body before menopause. Because estradiol interacts directly with the nervous system, this decrease often coincides with temporary changes in mood, behavior, and memory functioning.
Scientists aim to understand why some individuals experience persistent memory difficulties as they age, whereas others maintain their cognitive performance. “Menopause is an important neuroendocrine transition and with decades of life left to live after the transition it is important to understand how the brain adapts during this time,” said Abigail Testo, a postdoctoral associate in the Department of Psychiatry at the University of Vermont’s Larner College of Medicine.
Testo co-authored the study with Julie Dumas, a professor and vice chair in the same department. “We hoped with this research to add to the growing body of work being done to better understand how menopause contributes to normal or pathological aging,” Testo said.
A specific area of interest is episodic memory. This type of memory is the brain’s ability to recall specific past events or experiences, such as remembering a person’s name or recalling what happened yesterday.
To explore these individual differences, Testo and Dumas examined how estradiol levels relate to functional connectivity in the brain. Functional connectivity refers to the way distinct brain regions share signals and work together to perform specific tasks. Previous work indicates that estradiol plays a role in regulating these brain networks, but its exact influence during different stages of memory processing remains largely unexplored. The researchers aimed to see how estradiol levels affect the flow of information between brain regions when women encode new memories and when they recall them.
The researchers analyzed data from the Human Connectome Project Aging, a large database designed to track healthy brain aging. They looked specifically at 150 female participants between the ages of 40 and 55. This specific age range allowed the scientists to capture a wide spectrum of estradiol levels, as the group included women who were premenopausal, perimenopausal, and postmenopausal.
To measure hormone levels, medical technicians collected blood samples from the participants after an eight-hour fast. The average estradiol level among the participants was about 83 picograms per milliliter. On the same day, the women underwent functional magnetic resonance imaging, or fMRI. This imaging technique uses powerful magnetic fields to track blood flow in the brain, identifying which specific areas are active during different mental tasks.
During the brain scan, participants completed an episodic memory test called the Face-Name Encoding Task. In the first phase, called encoding, the women viewed faces paired with names and were asked to memorize them. After a brief distractor task, the recall phase began. During this stage, the same faces appeared without names, and the participants had to silently recall the correct names and press a button if they remembered them.
Following the scanning session, researchers tested the participants’ actual memory performance. They asked the women to match the correct names to ten of the faces they had just seen. Overall, the women performed quite well on this cognitive assessment. They correctly identified an average of about 7.5 out of 10 face-name pairs.
To analyze the brain imaging data, Testo and Dumas looked at the functional connections among 132 different regions of the brain. They also controlled for the age of the participants to ensure that chronological aging did not skew the hormonal data. They found five specific brain connections that were associated with estradiol levels during the recall phase of the memory task.
Specifically, higher levels of estradiol were linked to negative functional associations, meaning a decrease in synchronized activity, between certain brain areas. These decreased connections occurred between the left superior frontal gyrus and the brain stem, as well as between the right anterior middle temporal gyrus and the right posterior superior temporal gyrus. The frontal and temporal regions of the brain are well known for supporting human memory functions.
The authors suggest that the lower connectivity seen at higher estradiol levels might represent increased neural efficiency. In other words, with plenty of estradiol available, the brain might not need to work as hard or recruit as many strong connections to successfully recall the required information.
Despite the overall association between estradiol and brain connectivity, the researchers noted an unexpected detail regarding the specific menopausal stages. “We were surprised to find that these brain associations with estradiol levels were not found for women who were perimenopausal,” Testo said. “The reason this was a surprise is because perimenopause is a time with a lot of hormone variability and we thought that variability would lead to greater associations with brain functioning.”
Interestingly, the scientists found no statistically significant relationship between estradiol levels and brain connectivity during the initial encoding phase. This suggests that the hormone’s role differs depending on whether a person is actively learning new information or trying to access a stored memory. The researchers also found no statistically significant correlation between a participant’s estradiol levels and how well they actually scored on the memory test outside the scanner.
It is easy to misinterpret these brain connectivity differences as a direct indicator of everyday memory loss. Because the participants in this sample scored very high on the memory test, the data cannot establish if these specific brain connectivity patterns translate to noticeable memory deficits.
“While estradiol was associated with differences in functional association strengths, it was not similarly associated with differences in memory performance,” Testo explained. “For this reason, we can’t say if the identified functional associations are inherently good or bad for brain functioning.”
Still, the findings point to a lasting biological relationship. “Estradiol likely plays a role in brain functioning throughout the aging process, even after the reproductive period has ended,” Testo noted.
The study relies on a cross-sectional design, meaning it captures a single snapshot in time rather than tracking the same women over several years. This prevents drawing causal conclusions about an individual’s dropping estrogen levels directly causing the observed brain changes. People naturally have individual differences in their brain networks. Observing the exact same participants as they transition through menopause would provide stronger evidence of how hormonal changes alter brain function over time.
The scientists plan to address this gap in the future. “Future HCP-A releases (the dataset utilized in this study) will include longitudinal data,” Testo said. “It would be interesting to revisit this investigation as participants age and estradiol levels continue to fluctuate and decline.”
Future studies may also benefit from observing how other hormones that fluctuate during midlife interact with these brain networks. Hormones like progesterone also drop off after menopause, and observing their interaction with estradiol could offer a better biological picture.
Some participants in the current study used hormonal medications, which could influence brain connectivity differently than naturally produced hormones. Exploring the distinct effects of prescribed hormones versus natural hormones could offer a more detailed picture of cognitive aging in women.
The study, “Estradiol modulated brain connectivity in females during midlife performing an episodic memory task,” was authored by Abigail A. Testo and Julie A. Dumas.