Studies conducted in animals have provided robust evidence of how endocrine regulation impacts brain morphology on a rapid timescale. Over the course of hours to days, research involving rodents and non-human primates has demonstrated that estradiol and progesterone exert modulatory effects on various aspects of neuroplasticity.
These include cell proliferation, dendritic spine and synapse density, mitochondrial and synaptic health, synaptic sprouting, axon growth, and myelination. This body of evidence suggests a pivotal role of ovarian hormones in shaping the structural organization of the brain.
While an increasing number of studies have explored how these fluctuations affect brain function and behavior in humans, it remains less clear how these endocrine factors influence the structural changes in the brain, particularly over the rhythmic course of the menstrual cycle.
In this context, the hippocampus emerges as a key region known to exhibit significant neuroplasticity during the reproductive years. This neuroplasticity has been observed during various life events, such as pregnancy and the menstrual cycle. The hippocampus is also closely associated with emotional regulation and cognition, domains that are known to be susceptible to cycle-dependent fluctuations.
Furthermore, the hippocampus and the extended medial temporal lobe (MTL) are rich in estradiol and progesterone receptors, suggesting their significance in hormonal modulation. Previous studies have suggested that estradiol-dominant menstrual cycle phases are associated with greater hippocampal volume, although findings have been inconsistent. Most menstrual cycle studies assess only two timepoints and rely on cycle phase as a proxy for hormone states, rather than directly measuring ovarian hormone levels.
For instance, in a single-subject pilot study, subtle changes in gray matter density in the human hippocampus were found to parallel daily fluctuations in endogenous estradiol levels, while intrinsic functional connectivity changes were associated with endogenous progesterone levels across the menstrual cycle.
Additionally, the ’28andMe’ project has demonstrated that dense-sampling can reveal unique brain-hormone interactions in brain function and structure. Thus, while the hippocampus and the surrounding MTL appear to be promising targets for cycle-related hormonal modulation of structural brain plasticity, study designs must incorporate densely sampled hormone and neuroimaging data over the course of the entire menstrual cycle to capture the intra- and interindividual variability in both cycle variation and brain structure.
Furthermore, advancements in neuroimaging have allowed for more precise delineation of neuroanatomical subregions within the hippocampus and MTL in humans. These subregions exhibit unique cytoarchitecture, chemoarchitecture, and circuitry that differentially contribute to aging and disease. Different subregions play specific roles in memory processes and other cognitive functions. Consequently, hormone-modulated volumetric changes may manifest differently across the MTL subregions.
Research in animals, particularly focusing on the cornu ammonis 1 (CA1) subregion, which is critical for memory integration, has provided evidence of hormone-related changes in brain structure. Estradiol administration has been found to enhance synaptogenesis and spine density in CA1 neurons, while progesterone inhibits this effect. Additionally, the perirhinal area 35, a subregion associated with cognitive decline and early stages of dementia, has received little attention regarding endogenous ovarian hormone fluctuations in humans, despite its relevance to dementia progression and potential involvement in sex differences in Alzheimer’s disease pathology.
Methods
To shed further light on hormone-associated hippocampal and MTL changes in the female human brain during the reproductive years, this study provides a densely sampled and detailed ultra-high field neuroimaging dataset. This dataset was gathered from 27 healthy participants who underwent 7-Tesla magnetic resonance imaging (MRI) scanning during six menstrual cycle phases: menstrual, pre-ovulatory, ovulation, post-ovulatory, mid-luteal, and premenstrual.
To assess the influence of ovarian hormones on MTL subregions, the researchers employed the Automated Segmentation of Hippocampal Subfields software (ASHS), which allows for a sensitive approach to individual differences in MTL subregion morphology. The choice of the Magdeburg Young Adult 7T Atlas leveraged information on anatomical variability to provide more accurate delineation of subregions. Moreover, the 7-Tesla MRI images had small slice thickness and high in-plane resolution, enabling better delineation and segmentation of the MTL subregions.
To address the challenge of accurately characterizing menstrual cycle phases, a systematic protocol was developed. This overcame the limitations of previous work, which relied on less accurate menstrual cycle monitoring methods.
Results and Discussion
The study’s hypotheses were grounded in previous animal literature and a single-subject pilot study, which suggested that cycle-related increases in estradiol levels would be associated with increases in the volume of the whole hippocampus. Within the subregions, it was hypothesized that estradiol levels would be positively associated with perirhinal area 35 volume, and an interaction between estradiol and progesterone levels was expected in CA1 volume. The study also assessed other subregion volumes, such as CA2, CA3, subiculum, dentate gyrus, area 36, entorhinal cortex, and parahippocampal cortex, in an exploratory fashion.
The findings of this study will contribute to a better understanding of how endocrine factors shape healthy adult brain dynamics during the reproductive years. Understanding the impact of ovarian hormone fluctuations on the brain’s structural plasticity is crucial, especially as it pertains to female-specific cognitive decline risk. This knowledge will also inform more individualized strategies for neuroimaging the female brain.
Discussion: Unveiling the Impact of Ovarian Hormones on Memory Regions
This article presents an in-depth discussion of the findings and implications of a groundbreaking study that combines dense-sampling of hormones and high-resolution medial temporal lobe (MTL) segmentation analysis. The study sought to elucidate how fluctuations in the ovarian hormones, estradiol, and progesterone, influence memory-related brain regions, particularly the MTL and its subregions. The authors observed significant structural changes in specific subregions of the MTL, including the parahippocampal cortex, area 35, subiculum, and CA1, which correlated with hormone fluctuations across the menstrual cycle. These findings not only reveal the rapid and dynamic impact of ovarian hormones on brain structure but also challenge the traditional approach of analyzing the hippocampus as a single homogeneous structure.
Subregional Differences in Hormone Associations
The study results shed light on the distinct associations between hormone levels and MTL subregion volumes. It is noteworthy that estradiol levels were positively associated with parahippocampal cortex volume, while progesterone levels displayed a positive correlation with subiculum and area 35 volume. Notably, an interaction between estradiol and progesterone levels was observed in the CA1 subregion. These findings emphasize that different MTL subregions respond uniquely to ovarian hormones, highlighting the necessity of examining the brain at a subregional level rather than treating it as a homogenous structure.
CA1 and Area 35: Sites of Hormonal Influence
The study’s focus on CA1 and area 35 is particularly intriguing. Previous research has identified CA1 as vulnerable to memory impairment, and animal studies have shown that estradiol enhances synaptic plasticity in this subregion while progesterone has an inhibitory effect. The findings align with clinical studies indicating that estrogen replacement therapy may be beneficial for cognitive function in post-menopausal women. However, the role of progesterone in cognitive function is less clear, with some studies suggesting positive effects and others indicating limited or even negative impacts. The complexity of these findings suggests a need for further research into the interplay of ovarian hormones on brain regions relevant to cognition.
Progesterone’s Role in MTL Plasticity
The positive association between progesterone levels and area 35 volume, a subregion with clinical relevance to aging and cognitive decline, holds particular significance. As the risk of Alzheimer’s disease increases for women during periods of rapid ovarian hormone fluctuations, such as perimenopause, understanding how estradiol and progesterone affect brain structure is essential. This study offers a stepping stone for investigating the role of progesterone in MTL subregions that has been largely unexplored in previous research. The results suggest a complex interplay of hormones in influencing MTL subregion volumes, highlighting the need for additional investigations to replicate these findings and uncover the underlying mechanisms.
Potential Mechanisms: From Micro to Macro
While this MRI study cannot directly assess the microstructural processes responsible for changes in MTL morphology, the authors speculate on potential molecular and cellular mechanisms. Animal research indicates that ovarian hormones play critical roles in cell survival and plasticity, involving mechanisms such as cell proliferation, microglial activation, dendritic spine and synapse density, mitochondrial and synaptic health, synaptic sprouting, axon growth, and myelination. The presence of estrogen and progesterone receptors in the MTL further supports the notion that these hormones can impact the region at the microanatomical level.
However, it is important to note that changes in synaptic plasticity in regions like CA1, rather than neurogenesis in the dentate gyrus, appear to drive the observed changes in subregion volumes. This finding suggests that hormone-induced structural plasticity may be more focused on synaptic plasticity and remodeling in certain MTL subregions, especially CA1. The differential expression of hormone receptors across MTL subregions may be a mechanism for the observed subregion-specific volumetric changes.
Limitations and Future Directions
The study does acknowledge several limitations. First, the research was conducted in a healthy, European/German female population, and thus, generalizability to other populations and to males is limited. Future studies should consider populations with varying reproductive statuses and hormonal profiles. Additionally, the absence of a control group with clamped hormone levels, such as a hormonal contraception group, could provide valuable insights.
Furthermore, while this study focused on the MTL, ovarian hormones have widespread effects on various brain regions. Investigating hormone-modulated changes in structural and functional connectivity between MTL subregions and other areas, such as the prefrontal cortex, is warranted to capture a broader network understanding. The dense connectivity between the MTL and the prefrontal cortex is essential for cognitive and emotional processes.
Conclusion: A Leap Towards Understanding Hormone-Induced Neuroplasticity
In conclusion, this study is a significant step towards unraveling the impact of ovarian hormones on brain structural plasticity during the reproductive years. The findings provide compelling evidence that the MTL, particularly its subregions, undergo dynamic changes in response to subtle hormone fluctuations. By utilizing advanced neuroimaging techniques and individually derived segmentation analysis, this study overcomes the historical underrepresentation of female subjects and highlights the importance of studying endogenous hormone fluctuations.
Understanding the neuroplasticity of the MTL subregions in response to hormonal changes has implications for a wide range of neuropsychiatric and neurodegenerative diseases, including depression, Alzheimer’s disease, and other cognitive disorders. These conditions often affect women disproportionately, and the study contributes to the foundation for tailored treatments and interventions to mitigate the impact of hormone-related cognitive decline. The future of research in this area holds promise for improving the generalizability of structural volumetric changes in the human brain, offering insights into the mechanisms underlying hormone-induced neuroplasticity, and ultimately advancing the understanding and treatment of neurological and psychiatric conditions, especially in women.
reference link : https://www.nature.com/articles/s44220-023-00125-w#Sec6
