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Even though women are disproportionately affected by brain diseases like Alzheimer’s and depression, brain research seldom focuses on female-specific issues, like the connection between female sex hormone fluctuations and brain health.

Women go through an average of nearly 450 menstrual cycles throughout their life. The menstrual cycle is a roughly 29-day period during which the blood levels of the sex hormones estrogen and progesterone fluctuate in preparation for possible pregnancy. Even though most women are well aware of the relationship of their cycle with mood fluctuations, it has only recently become known that this cycle affects specific brain regions involved with emotions, memory, and behavior.

“…the same hormones that regulate the menstrual cycle also influence the brain’s architecture.”

Recent brain imaging studies using magnetic resonance imaging (MRI) have unveiled that the female adult brain can experience significant dynamic changes in structure and function in synchronization with the menstrual cycle. Research largely performed in animal models has demonstrated how the same hormones that regulate the menstrual cycle also influence the brain’s architecture. Specifically, the female sex hormones estrogen and progesterone play a significant role.

During the menstrual cycle, estrogen initially rises to thicken the uterus lining and then drops to allow ovulation. Subsequently, both estrogen and progesterone increase in case of fertilization and then decrease if pregnancy doesn’t occur, leading to menstruation. This hormonal ebb and flow is accompanied by changes in brain structures like the hippocampus, a key region involved in cognition, emotion and memory, which is densely packed with receptors for these hormones. The hippocampus responds dynamically to life experiences and can indicate early signs of dementia if it shrinks.

According to the scientific literature: “ovarian hormones are powerful modulators of neuroplasticity, with animal research offering robust evidence of endocrine regulation of brain morphology on a timescale of hours to days…rodent and non-human primate studies have demonstrated that estradiol (the major estrogen in the blood) and progesterone elicit modulatory effects on several aspects of neuronal microstructure and proliferation.”

“…estradiol levels increase eightfold and progesterone levels 80-fold over a period of ~25–32 days.”

In humans, the menstrual cycle provides an opportunity to study how endogenous fluctuations in sex hormones transiently influence the brain, as estradiol levels increase eightfold and progesterone levels 80-fold over a period of ~25–32 days. Although a growing number of menstrual cycle studies suggest that ovarian hormone fluctuations do influence brain function and behavior in humans, it remains less clear how endocrine factors may shape brain structure following the rhythmic nature of the menstrual cycle, and the implications this would have for human adult neuroplasticity, brain function and behavior associated with the menstrual cycle.

The hippocampus is a key region shown to display a remarkable degree of neuroplasticity during the reproductive years, such as pregnancy and during the menstrual cycle. The hippocampus, which is rich in estradiol and progesterone receptors also plays a key role in modulating the brain’s stress response, and is also implicated in emotional regulation and cognition. In animal studies, chronic stress has previously been shown to lead to a reduction of hippocampal volume, while estrogen treatment was able to reverse these changes.

Recently, a novel approach using so called “dense-sampling” of hormones and brain across the menstrual cycle has been developed. Compared to sampling approaches, which typically just measure cycle phases corresponding to peak/trough hormone concentrations, so called “dense-sampling” designs assess many menstrual cycle stages to better capture dynamic interactions between the endocrine and nervous systems. For example, the ‘28andMe’ project has also elegantly shown that dense-sampling (n = 1 female participant, sampled 30 days across the full menstrual cycle, 30 days on a hormonal contraceptive regimen) can uncover unique brain–hormone interactions in brain function and structure that would otherwise be overlooked.

“…CA1 neurons are critically involved with the formation, consolidation and retrieval of hippocampal-dependent memories.”

Moreover, although most human magnetic resonance imaging (MRI) studies have treated the hippocampus as a homogeneous structure, recent advances in high resolution neuroimaging allow for more precise delineation of neuroanatomical and functionally distinct subregions of the hippocampus, such as the dentate gyrus and CA1 region and the medial temporal lobe (MTL) in humans. Within the hippocampal memory system, CA1 neurons are critically involved with the formation, consolidation and retrieval of hippocampal-dependent memories. This specificity is important given the unique cytoarchitecture, chemoarchitecture and circuity of these subregions that differentially contribute to aging and disease.

Taking advantage of the insights from rodent studies, and employing new imaging techniques to study the brain – hormone connection, Dr. Julia Sacher’s team at the Max Planck Institute for Human Cognitive and Brain Sciences, in Leipzig, Germany used advanced ultrahigh-field MRI to study these effects in high temporal and spatial resolution. Their findings with first author Rachel G. Zsido were published in August 2023 in the prestigious journal, Nature Mental Health. The investigators were able to observe that different parts of the hippocampus changed in thickness in sync with the hormonal changes of the menstrual cycle. For example, rising estrogen levels thickened the outer layer of the hippocampus, which then contracted when progesterone levels rose.

They were able to demonstrate how estradiol and progesterone fluctuations affect key memory regions, such as the CA1 and MTL hippocampal subregions. More specifically, estradiol levels were positively associated with parahippocampal cortex volume, and progesterone levels were positively associated with the volume of other subregions, such as the subiculum and area.

“…estrogen replacement is associated with maintaining cognitive function in older age.”

Women are more likely to suffer from cognitive impairment when ovarian hormones rapidly fluctuate, such as during perimenopause. The hypothesized interaction in CA1 is in agreement with previous animal work, showing that estradiol enhances synaptic structure and function while subsequent increases in progesterone seem to inhibit this effect. Although studies in humans are limited and larger brain volume does not necessarily imply better function, there is agreement that the CA1 subregion of the hippocampus plays a distinct functional role in memory integration and inference. Clinical studies in post-menopausal women have also shown that estrogen replacement is associated with maintaining cognitive function in older age.

The research published by Dr. Sacher’s team highlights the need for more studies focusing on the interaction between female sex hormones and brain function, and the role of sex as an important factor in women’s health, an area neglected in Neuroscience research.

For the past 15 years, with funding from the Office of Research on Women’s Health and NIDDK, the UCLA Specialized Center of Research Excellence (SCORE) has done such pioneering studies on sex related differences in the brain with a focus on brain gut microbiome interactions in chronic intestinal diseases, such as irritable bowel syndrome.

As a response to the neglect of women’s health research by governmental and private organizations, President Biden announced the first-ever White House Initiative on Women’s Health Research on Nov 13, 2023, an effort led by First Lady Jill Biden and the White House Gender Policy Council. The overall goal of this initiative is threefold:

1. Deliver concrete recommendations to advance women’s health research.
2. Take a targeted, high-impact approach.
3. Engage the scientific, private sector, and philanthropic communities.

Despite making up more than half the population, women have historically been understudied and underrepresented in health research. The new Initiative will fundamentally change how we approach and fund women’s health research, and pioneer the next generation of discoveries in women’s health.

The new White House Initiative is committed to galvanizing the Federal government and the private and philanthropic sectors to spur innovation, unleash transformative investment to close research gaps, and improve women’s health.

The significance of the Sacher study is not only in their implications for understanding brain plasticity, but also for tailoring medical treatments and interventions to one of the most prevalent health conditions in the population and to better understand the greater propensity of women to develop Alzheimer’s disease. They suggest that hormonal fluctuations could be linked to various experiences women report, like mood swings during the menstrual cycle. The current lack of focused research on women’s brains, especially in the context of significant healthcare concerns such as Alzheimer’s, highlights the need for a deeper investigation into the neurobiological underpinnings of women’s health.