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From Menstruation to Menopause: How Hormonal Shifts Shape Women's Brain Health

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Women's health is a vital area of medical research, yet it has historically been underrepresented in many scientific fields. Encompassing a wide range of physical, emotional and social factors that uniquely impact half of the global population, women face distinct health challenges shaped by their biological and reproductive systems. Cardiovascular health, autoimmune diseases and mental health also often present differently in women than in men. Despite this, women’s health has historically been underfunded and under-researched, leading to disparities in diagnosis, treatment and care.

 

In recent years, there has been a growing recognition of the need to address these gaps, particularly in areas such as brain health. Women experience unique physiological events throughout their lives – from puberty and menstruation to pregnancy, menopause and more – that significantly affect their brains. Each of these stages presents unique challenges, influencing mental health, cognition and neurological function in ways that are only now being uncovered.

 

The menstrual cycle, for example, introduces hormonal fluctuations that can influence mood and cognition. Certain neurological conditions like migraines or mood disorders can also be impacted by these hormonal shifts. During pregnancy, dramatic changes in estrogen and progesterone levels alter brain structures and function. Another wave of hormonal shifts is seen in later life during the menopause.


Emerging research underscores the importance of focusing on women’s brain health. Statistics show that women are more likely than men to develop certain neurological conditions, including anxiety and depression. Women also account for nearly two-thirds of Alzheimer’s cases. Despite this, much of neuroscience research has traditionally centered on male physiology, leaving gaps in our understanding of the female brain.

The menstrual cycle

The menstrual cycle is a complex biological process that triggers numerous physiological and psychological changes. Driven by a cyclical wave of hormonal fluctuations, the typical monthly cycle can have a significant impact on women’s health and well-being. Recent research has increasingly focused on understanding how these hormonal shifts impact brain network dynamics, cognitive function and structural brain plasticity. Considering female sex hormone levels can change by over 100% in 24 hours, understanding their role in brain health is essential for addressing mood, cognition and overall mental well-being in women.


Menstrual cycle phases

  1. Menstruation (days 1–5): The uterine lining sheds, triggered by a decrease in estrogen and progesterone levels
  2. Follicular phase (days 6–14): The pituitary gland releases follicle-stimulating hormone (FSH), prompting the maturation of ovarian follicles. These follicles, in turn, produce estrogen, initiating the thickening of the uterine lining in preparation for potential pregnancy
  3. Ovulation (day 14): There is a surge in luteinizing hormone (LH) that triggers the release of a mature ovum from the ovary
  4. Luteal phase (days 15–28): The ruptured follicle transforms into the corpus luteum, secreting progesterone to maintain the uterine lining in anticipation of implantation

Brain network dynamics across the menstrual cycle

A recent study from Pompeu Fabra University, published in npj Women’s Health, used functional magnetic resonance imaging (fMRI) to investigate how brain network dynamics change throughout the menstrual cycle.

 

The researchers analyzed resting state brain activity in 60 women across the early follicular, pre-ovulatory and mid-luteal phases of the menstrual cycle. They specifically analyzed how different brain networks involved in attention, emotions and introspection evolved during the resting state.

 

The study revealed that hormonal fluctuations, particularly in estrogen and progesterone levels, significantly modulated brain network dynamics. Brain complexity – the variability and richness of the brain’s activity patterns over time – peaked during the pre-ovulatory phase when estrogen levels were highest, with complexity being at its lowest during the early follicular phase when progesterone levels began to rise.

 

These changes highlight the role of ovarian hormones, providing further insight into the cognition, mood and behavior of healthy women as well as those impacted by menstrual cycle-related disorders.

Hormonal rhythms and brain structure

Fluctuations in ovarian hormones also influence structural changes in the brain during the menstrual cycle, according to another study published in Nature Mental Health, from the Max Planck Institute.

 

Using ultra-high field 7 Tesla (7T) MRI scans, the team focused on the medial temporal lobe and hippocampus, areas known for their role in memory and spatial cognition. They scanned 27 women at 6 specific points during their cycle to capture how these brain regions adapted to hormonal changes.

"We were able to determine that these brain areas remodel themselves in synchronization with the menstrual cycle,” said  Dr. Julia Sacher, a professor in the department of neurology at the Max Planck Institute.

Certain subregions of the medial temporal lobe expanded when estradiol levels rose, particularly during the pre-ovulatory phase, while these changes were less visible when progesterone levels increased later in the cycle.

 

The team plans to investigate whether these rhythmic changes may be altered in individuals at risk for memory and affective disorders.

The menstrual cycle’s effect on sports cognition

Researchers from University College London (UCL) and the Institute of Sport, Exercise & Health (ISEH) published a study in Neuropsychologia that explored how hormonal fluctuations during the menstrual cycle impact cognition and athletic performance.

 

The study involved 241 participants, including 105 menstruating females, and used sport-related cognition tests to measure reaction times, spatial awareness and accuracy across different phases of the menstrual cycle.

 

Contrary to popular belief, the results found participants performed better during menstruation, demonstrating faster reaction times and higher accuracy on cognitive tasks. In contrast, during the luteal phase – when progesterone levels peak – reaction times were slower, which could potentially increase the risk of sports-related injuries. Participants were on average 10–20 milliseconds slower compared to any other cycle phase.

 

“Research suggests that female athletes are more likely to sustain certain types of sports injuries during the luteal phase and the assumption has been that this is due to biomechanical changes because of hormonal variation. But I wasn’t convinced that physical changes alone could explain this association,” said Dr. Flaminia Ronca, associate professor at UCL division of surgery and interventional science and ISEH.

 

“There’s lots of anecdotal evidence from women that they might feel clumsy just before ovulation, for example, which is supported by our findings here. My hope is that if women understand how their brains and bodies change during the month, it will help them to adapt,” said co-author Dr. Megan Lowery, a researcher at UCL surgery and interventional science and ISEH.

Pregnancy

Pregnancy is a period marked by profound physical and hormonal changes that extend beyond preparing the body for childbirth. While physical changes like weight gain, metabolic adjustments and increased blood flow are well-documented, our understanding of how pregnancy affects the brain remains relatively unexplored. Recent studies have begun to shed light on how pregnancy may lead to permanent neurological changes, revealing alterations that have significant implications for maternal health. Furthering our understanding of these changes could help improve early detection and treatment of conditions such as postpartum depression, preeclampsia and other perinatal mental health issues.  

Comprehensive mapping of brain changes during pregnancy

A study from the University of California, published in Nature Neuroscience, offers one of the first detailed maps of how the brain changes during pregnancy. Researchers used advanced imaging techniques to track neurological changes in a healthy 38-year-old woman from 3 weeks pre-conception through to 2 years postpartum. The results were compared with non-pregnant controls.

“Over 80% of the brain regions we studied had reductions in gray matter volume,” said co-author Dr. Elizabeth Chrastil, an associate professor at the University of California, Irvine.

These changes were observable as early as the ninth week of pregnancy and persisted up to two years postpartum. White matter microstructure also increased significantly during the first and second trimesters, although returned to baseline after childbirth.

 

While the study only involved a single participant, it lays the groundwork for understanding pregnancy-related brain changes, which could help address conditions such as postpartum depression and preeclampsia earlier.

The impact of the TRPC5 gene on maternal behavior and brain function

TRPC5, located on the X chromosome, plays an important role in processing sensory signals. A study from the University of Cambridge, published in Cell, investigated how the gene influences maternal behavior, postnatal depression and obesity. The team examined two male patients and their mothers, all of whom had a deletion in the TRPC5 gene, resulting in obesity, anxiety and behavioral issues.

 

The gene deletion affected the hypothalamus, influencing oxytocin-producing neurons that regulate maternal behaviors. Mouse models with similar TRPC5 deficiencies exhibited behaviors like those observed in the human subjects, including weight gain, anxiety and depressive symptoms in the maternal mice. Restoration of the gene improved these symptoms, suggesting a strong link between TRPC5 and oxytocin.

 

“While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition,” said Dr. Sadaf Farooqi, a professor from the institute of metabolic science at the University of Cambridge.

Menopause

The menopause is a natural part of aging that typically occurs in women during midlife, marking the end of menstruation. This transition is driven by a drastic decline in estrogen levels, impacting the body and brain. Perimenopause occurs before a woman is classed as menopausal. This period is characterized by physical symptoms like hot flushes, weight gain and irregular periods, and can last as little as a few months or as long as four years. Perimenopause is also associated with various neuropsychiatric symptoms including mood swings, depression and cognitive difficulties – often referred to as "brain fog". Menopause is officially defined as the stage when the ovaries produce insufficient estrogen to release eggs, resulting in the end of menstruation.

 

Emerging research is now focusing on how these hormonal shifts influence brain structure and function, aiming to understand the underlying mechanisms behind the cognitive and mood changes experienced by many. Investigating these neurological effects is vital for developing effective interventions and therapies to support women through this life stage.

Tracking estrogen activity in the menopausal brain

A recent study by Weill Cornell Medicine, published in Scientific Reports, used a novel brain imaging technique to investigate the neurological changes that occur as estrogen levels decline during menopause.

 

The team used positron emission tomography  imaging with a tracer (18F-fluoroestradiol) to measure estrogen receptor (ER) density in the brains of 54 healthy women aged 40–65 years, categorized as premenopausal, perimenopausal or postmenopausal. The researchers also collected self-reported data on menopausal symptoms and cognitive performance using a menopause health questionnaire.

 

They observed higher ER density in postmenopausal women, particularly in regions linked to memory and mood, such as the hippocampus, frontal cortex and thalamus. The increases in ER density were linked to declines in cognitive function, including memory performance, and were associated with mood changes, like depression, when observed in the thalamus.

 

The team were also able to accurately distinguish menopausal status based on ER density, independent of age.

 

The researchers are now planning further investigations into how estrogen therapy might influence ER density and alleviate menopausal symptoms. 

Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is a common hormonal disorder affecting up to 8–13% of women. It is characterized by elevated androgen levels, irregular menstrual cycles and symptoms such as excessive hair growth, acne and infertility.

“While it [PCOS] has been linked to metabolic diseases like obesity and diabetes that can lead to heart problems, less is known about how this condition affects brain health,” said Dr. Heather G. Huddleston, MD, from the University of California, San Francisco.

PCOS and cognitive decline

Huddleston and her team examined the long-term effects of PCOS on brain health, particularly cognitive function, in their study published in Neurology by the American Academy of Neurology. They followed 907 women aged 18–30 years at the start of the study for 30 years, including 66 individuals with PCOS, who took part in several tests to measure their memory, verbal abilities, processing speed and attention.

 

Women with PCOS scored lower on three out of five tests, showing a significant decrease in memory, attention and verbal skills compared to those without PCOS. In one activity, measuring attention ability, those with PCOS scored 11% lower on average compared to those without the condition.


Brain scans from a smaller subset of participants, at years 25 and 30 of the study, revealed that those with PCOS had reduced white matter integrity, suggesting early signs of brain aging.


“Making changes like incorporating more cardiovascular exercise and improving mental health may serve to also improve brain aging for this population,” said Huddleston.

Enhancing women’s health

As research continues to provide mounting evidence that the distinct challenges women face, throughout their lives, are intrinsically linked to brain function and health, we are faced with closing the historical gap in understanding the female brain. Advancements in neuroimaging and hormonal analysis are starting to highlight how these biological processes impact cognition, mood and mental health. By deepening our knowledge in these areas, we can better tailor interventions and therapies, ultimately improving women's health and quality of life throughout different life stages.

 

References:

  1. Avila-Varela DS, Hidalgo-Lopez E, Dagnino PC, et al. Whole-brain dynamics across the menstrual cycle: the role of hormonal fluctuations and age in healthy women. npj Women’s Health. 2024;2(1):8. doi: 10.1038/s44294-024-00012-4
  2.  Zsido RG, Williams AN, Barth C, et al. Ultra-high-field 7T MRI reveals changes in human medial temporal lobe volume in female adults during menstrual cycle. Nat Mental Health. 2023;1(10):761-771. doi: 10.1038/s44220-023-00125-w
  3.  Ronca F, Blodgett JM, Bruinvels G, et al. Attentional, anticipatory and spatial cognition fluctuate throughout the menstrual cycle: potential implications for female sport. Neuropsychologia. 2024:108909. doi: 10.1016/j.neuropsychologia.2024.108909
  4.  Pritschet L, Taylor CM, Cossio D, et al. Neuroanatomical changes observed over the course of a human pregnancy. Nat Neurosci. 2024. doi: 10.1038/s41593-024-01741-0
  5.  Li Y, Cacciottolo TM, Yin N, et al. Loss of transient receptor potential channel 5 causes obesity and postpartum depression. Cell. 2024. doi: 10.1016/j.cell.2024.06.001
  6.  Mosconi L, Nerattini M, Matthews DC, et al. In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology. Sci Rep. 2024;14(1):12680. doi: 10.1038/s41598-024-62820-7
  7.  Huddleston HG, Jaswa EG, Casaletto KB, et al. Associations of polycystic ovary syndrome with indicators of brain health at midlife in the cardia cohort. Neurology. 2024. doi: 10.1212/WNL.0000000000208104