The Neuroscience of 
Perimenopause

Perimenopause marks a natural transition for women preceding menopause. The primary symptoms of perimenopause include irregular periods, hot flashes, night sweats, sleep disturbances, and mood swings. For most women, these symptoms appear in their 40s but for many they appear almost a decade earlier. If you're already noticing these changes, this article is especially relevant to you, as well as anyone curious about the neurological shifts that lie ahead.


As this Nature article points out, while the clinical definition of perimenopause focusses on functional changes in the reproductive system, the symptoms are largely neurological. The paper characterises perimenopause as a "neurological transition state," addressing a crucial perspective that is often missing in current discourse, diagnosis, and treatment: the neuroscience of perimenopause. This newsletter summarises the latest research surrounding brain changes during this critical phase in the hope of validating your experiences by connecting them to real, researched changes in the brain and body.

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What’s causing the neurological changes?

Most women transition through perimenopause without long-term adverse effects; however, a substantial proportion of women emerge from this transition with an increased risk of neurological decline. Oestrogen, a master regulator within the brain, coordinates signalling pathways that regulate brain activity and function. During perimenopause, the connection between oestrogen and the brain's energy system breaks down. This disruption can lead to a state where the brain doesn’t metabolise energy as effectively, potentially causing neurological dysfunction. During this transition, even minor signs of neurological issues can be early warnings of future neurological decline.

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These changes are real and visible

Recent studies have shown that significant changes occur in the brain during perimenopause, impacting both its structure and how it functions. This study published in the Menopause Journal confirms that changes in functional connectivity and brain structure, such as alterations in ALFF (Amplitude of Low Frequency Fluctuations) and GMV (Gray Matter Volume), are evident during this transition. These neurological changes are likely linked to common cognitive symptoms experienced during perimenopause, including anxiety, brain fog, fatigue, headaches, and depression.

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Neuroplasticity, essential for memory and learning, decreases

Research in mice has shown a reduction in synaptic plasticity during the transition to irregular menstrual cycles—a stage analogous to human perimenopause. While these findings have yet to be confirmed in humans, they indicate that a decline in neuroplasticity may start earlier than previously recognised, potentially impacting cognitive functions well before a woman reaches menopause. Reduced neuroplasticity can lead to difficulties in learning new information or adapting to new situations, which might contribute to the cognitive challenges often reported during perimenopause, such as memory lapses and decreased mental flexibility.

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Biomarkers of depression are often present

Recent research has identified specific chemicals in the blood—known as biomarkers—that can predict depression in women going through this critical life stage. Changes in these biomarkers are considered risk factors for developing depression. These chemicals include C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and brain-derived neurotrophic factor (BDNF). In a study of 73 women, those experiencing self-assessed depression had higher levels of CRP, IL-6, and TNF-α, and lower levels of BDNF compared to those who were not depressed. Understanding these biomarkers could lead to improved diagnosis and treatment, offering doctors a way to identify and address depression more effectively in women during perimenopause.

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Perimenopause marks a huge risk factor for Alzheimer’s

Perimenopause is a significant risk factor for Alzheimer's disease, primarily due to changes in how the brain manages energy during this phase. As explained earlier, during perimenopause, oestrogen's regulation of cerebral glucose metabolism decreases, leading to reduced glucose processing and availability in the brain. This reduction results in a decline in your cell’s energy efficiency that continues into menopause, marking a critical risk factor for Alzheimer's (Mosconi et al., 2017). This suggests that interventions for Alzheimer’s in women should focus on the perimenopausal stage to have the most impact in mitigating disease onset.

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There's still a lot we don't know 


We still know very little about the perimenopausal brain, mostly because it's a stage of women's lives that isn't very clear in terms of diagnosis and age, and even medical records rarely mention clinicians assessing women for perimenopausal symptoms. As a result younger women experiencing perimenopausal symptoms are often excluded from those studied. This by no means indicates that perimenopause is a homogenous experience, but that we need more resources addressing the wide range of possibilities when it comes to this hormonal shift.

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Brain-based solutions show promise

We've been refining in-clinic treatments for depression and cognitive dysfunction to bring women accessible at-home technologies that target the source of neurological changes: the brain. While our solution, Nettle, was built for the management of PMS and menstrual pain, it has the potential to transform how perimenopausal women treat their symptoms because of the similarity of symptoms, and regions of the brain impacted by hormonal changes. Nettle specifically targets the dorsolateral prefrontal cortex, which is responsible for emotional regulation and cognitive function. Our technology works on your symptoms by reprogramming your brain to perceive them differently, bringing you relief directly from the source.

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Order Nettle today to benefit from our 90-day trial policy, starting from the day you receive it.