Clues about Longevity in Estrogen & PCOS

There is an intricate relationship between Polycystic Ovary Syndrome (PCOS), sex hormones (estrogen and androgens), and cognitive function. Recent research has demonstrated specific cognitive deficits in individuals with hyperandrogenic PCOS, particularly in executive functions, often exacerbated by insulin resistance.1 A There are multifaceted mechanisms through which estrogen and androgens influence brain health, from their roles as neurosteroids produced within the brain to their modulation of neurogenesis, synaptic plasticity, neurotransmitter systems, and neuroinflammation via diverse receptor pathways.2 There is a complex interplay of hyperandrogenism, insulin resistance, and inflammation as key drivers of PCOS-related cognitive alterations, which can lead to structural brain changes like reduced white matter integrity, even in younger adults.11 This research in the way that PCOS implicates traditional brain functioning in females can be extrapolated to broader findings about estrogen’s enduring neuroprotective impact across the lifespan, its role in cognitive aging and neurodegenerative diseases, and the potential for targeted hormonal and lifestyle interventions to preserve brain health.8

Introduction: Hormonal Influences on Brain Health

Polycystic Ovary Syndrome (PCOS) is a highly prevalent endocrine disorder affecting an estimated 7-10% of women of childbearing age.13 It is primarily recognized for its reproductive manifestations, including oligomenorrhea (infrequent menstruation), hyperandrogenism (elevated androgen levels), and infertility.12 Beyond its well-known reproductive and cutaneous sequelae (aka cystic acne), PCOS is increasingly understood as a multi-system disorder associated with a significant adverse cardiometabolic profile. This profile commonly includes insulin resistance, obesity, dyslipidemia, hypertension, and chronic inflammation, all of which contribute to a heightened risk of conditions like type 2 diabetes.12 The systemic metabolic and hormonal disruptions characteristic of PCOS are now recognized to extend their influence to brain structure and function, impacting mental health and cognitive outcomes across the lifespan.13

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis, including estrogens and androgens, are not merely peripheral regulators of reproductive function but also potent neurosteroids.4 These steroid hormones exert profound and multifaceted effects on the development, maintenance, and ongoing function of the central nervous system throughout an individual's life.20 They are intricately involved in modulating fundamental neurobiological processes such as neural differentiation, proliferation (neurogenesis, the act of building new brain circuits), and synaptic plasticity.2 Furthermore, these hormones influence various neurotransmitter systems, collectively supporting cognitive resilience and adaptive brain remodeling.2 The observed sex differences in cognitive functioning, as well as in the vulnerability and manifestation of several psychiatric and neurological diseases—such as Alzheimer's disease (AD) and schizophrenia—strongly underscore the pervasive influence of these sex hormones on overall brain health and disease trajectories.4

Cognitive impacts observed in individuals with PCOS is not broadly discussed, despite an evolving landscape of research demonstrating the clear role of estrogen/androgen in shaping brain anatomy and function.1 The intricate molecular and cellular mechanisms by which estrogen and androgens influence brain function are critical for understanding the way in which estrogen could impact the brain. While research is evolving in this space, elevating recent findings is pertinent to the broader conversation. There are many implications of these hormonal influences for understanding general brain health, cognitive aging, and neurodegenerative disease risk, thereby integrating specific PCOS findings into a wider neuroendocrinological context. We are simultaneously excited about the research to date and eager for further focus on these critical insights for the overall field of women’s health.

Cognitive Function in Polycystic Ovary Syndrome (PCOS): Specific Findings and Broader Evidence

The investigation into cognitive function in reproductive-aged individuals with PCOS has yielded significant findings, highlighting specific areas of vulnerability. (A seminal study categorized subjects into two groups: hyperandrogenic NIH-PCOS (n=35), characterized by clinical or biochemical hyperandrogenism alongside oligomenorrhea or polycystic ovaries, and non-androgenic PCOS (n=13), presenting with only oligomenorrhea and polycystic ovaries without hyperandrogenism.1)

hyperandrogenism is a medical condition characterized by elevated levels of androgens, often referred to as "male hormones" like testosterone, which are critical for women's health when in balance. While it can occur in both sexes, it is more common in women.

In women, hyperandrogenism is a clinical characteristic of Polycystic Ovary Syndrome (PCOS), affecting 60-80% of women with the condition and accounting for about 70% of hyperandrogenism cases overall. When androgen levels are high and out of balance, they can contribute to a range of hormonal, metabolic, reproductive, and psychological issues. Symptoms may include acne, seborrhea, hair loss on the scalp, increased body or facial hair (hirsutism), and infrequent or absent menstruation. Complications can also include high blood cholesterol and diabetes

A core finding of this study was that individuals with hyperandrogenic (high androgen) NIH-PCOS demonstrated significantly lower relative performance in executive functions when compared to their non-androgenic counterparts.1 This deficit was not generalized but specific, manifesting in subdomains such as verbal fluency, working memory, and cognitive control. These functions were assessed using a battery of neuropsychological tests, including the Delis-Kaplan System (Stroop, Trail Making for cognitive control; Design and Verbal Fluency for generativity) and Wechsler Adult Intelligence Scale (WAIS) Digit Span and Wechsler Memory Scale Symbol Span for working memory.1 The study further revealed that among NIH-PCOS subjects, those with co-occurring insulin resistance exhibited the lowest performance on the composite executive function score. This observation underscores that insulin resistance acts as a significant exacerbating factor for cognitive impairment in this population.1 Importantly, cognitive performance on measures of "pre-morbid" IQ, such as verbal and perceptual reasoning (measured with WAIS) and processing speed (measured by WAIS symbol search), was found to be similar between the hyperandrogenic and non-androgenic PCOS groups.1 This suggests that the observed executive function deficits are not indicative of a generalized intellectual impairment but rather a specific impact on higher-order cognitive processes. The findings from this study strongly suggest a direct or indirect causal link between hyperandrogenism (high androgenism), a defining feature of NIH-PCOS, and these specific executive function deficits. The exacerbation of these deficits by insulin resistance further points to a complex interplay of hormonal and metabolic factors. The preservation of "pre-morbid" IQ implies that these are acquired, domain-specific impairments rather than global neurodevelopmental issues, indicating that the hormonal and metabolic dysregulation in PCOS might selectively impair neural circuits involved in these higher-order functions.

Beyond this initial study, a growing body of evidence consistently links PCOS to cognitive alterations across different age groups. Longitudinal studies, such as the Coronary Artery Risk Development in Young Adults (CARDIA) Women's study, have tracked women with and without PCOS over a 30-year period. These studies revealed that women with PCOS at midlife (average age 54.7 years) performed significantly lower on tests of executive function (Stroop Interference Test), memory (RAVLT Long Delay Recall), and verbal abilities (Category Fluency).11 Notably, for the test measuring attention, participants with PCOS had an average score approximately 11% lower than those without the condition.16 Beyond functional deficits, these longitudinal investigations also revealed structural brain changes, specifically lower total white matter fractional anisotropy, a measure indicative of reduced white matter integrity.11 White matter is crucial for efficient information processing and connecting brain regions responsible for learning, balance, focusing, and problem-solving.16

Moreover, alterations in white matter microstructure have been observed even in younger adult women with PCOS.

White matter is crucial for efficient brain function because it helps the brain process information and connects different areas of the brain. These connections are vital for various cognitive processes, including learning, maintaining balance, focusing attention, and problem-solving. Changes in white matter integrity, such as those observed in conditions like PCOS, can be an early indicator of alterations in the brain that may occur with aging or other health conditions.

Studies involving individuals with PCOS (average age 31 years) demonstrated altered white matter microstructure, characterized by a widespread reduction in axial diffusivity (diffusion along the main axis of white matter fibers) and increased tissue volume fraction (the proportion of volume filled by white or grey matter) in regions like the corpus callosum.15 These structural changes were accompanied by subtle decrements across a broad range of cognitive tests, notably independent of age, education, and body mass index (BMI).15 The consistent findings across studies, from reproductive-aged to midlife women, and the detection of white matter alterations in young adults, strongly suggest that PCOS is associated with a long-term trajectory of accelerated cognitive aging and early-onset structural brain changes.

Altered white matter microstructure, specifically reduced axial diffusivity and increased tissue volume fraction in areas like the corpus callosum, indicates compromised brain communication pathways. White matter is crucial for efficient information processing, learning, and problem-solving. These structural changes are linked to subtle declines across various cognitive tests. Importantly, these alterations are independent of age, education, and BMI, suggesting that the underlying condition (like PCOS) directly impacts brain health and function, even in younger adults.

These findings imply that the condition's impact on the brain is not merely a late-life phenomenon but begins much earlier, potentially setting the stage for future cognitive decline. The fact that changes are observed independently of age, education, and BMI in younger adults indicates that the underlying PCOS pathophysiology itself, rather than just aging or obesity, drives these brain alterations.

The following table summarizes the cognitive domains affected in PCOS and the associated factors identified in the research:

Table 1: Summary of Cognitive Domains Affected in PCOS and Associated Factors

3. Mechanisms of Estrogen's Influence on Brain Function

Estrogen, particularly 17β-estradiol (E2), is classically recognized as a primary endocrine signal produced by the ovary, essential for female reproduction. However, E2 is also a potent neurosteroid, meaning it can be synthesized locally within the brain by neurons and astrocytes in both men and women.2 This local production, often referred to as neuron-derived E2 (NDE2), allows for intricate, localized control over brain function, potentially independent of systemic ovarian fluctuations.2 E2 is a lipophilic steroid, enabling it to readily diffuse through the blood-brain barrier (BBB) to reach the brain parenchyma, where it regulates diverse processes linked to development, reproduction, emotion, and cognition.4 The presence of neurosteroidogenesis, the local synthesis of estrogen within the brain, implies a sophisticated, localized regulatory system for brain function. This mechanism could allow the brain to buffer systemic hormonal fluctuations and maintain a stable microenvironment, or conversely, contribute to localized dysregulation in pathological states if this local synthesis is impaired or overwhelmed by peripheral imbalances.

Estrogen exerts its profound effects by binding to specific estrogen receptors (ERs). Three main subtypes have been identified: Estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled estrogen receptor 1 (GPER1).4 These receptors mediate estrogen's influence through two primary signaling pathways:

• Classical Genomic Actions: ERα and ERβ belong to the steroid-activated nuclear receptor family of transcription factors. Upon E2 binding, these receptors undergo conformational changes, dissociate from associated heat shock proteins, and then homo- or hetero-dimerize. The activated dimers translocate to the nucleus, where they recruit coactivators and bind to specific DNA sequences known as estrogen response elements (EREs).4 This binding mediates the transcription of target genes involved in cellular proliferation, differentiation, and survival.4 This classical genomic pathway is typically slower, leading to long-term cellular changes crucial for brain development and maintenance.5
• Rapid Non-Genomic Actions: In addition to classical genomic actions, ERs can also mediate rapid, non-genomic effects that do not directly involve DNA binding.4 These actions occur through membrane-bound estrogen receptors (mERs) or via transcriptional cross-talk, where ERs interact with other transcription factors or activate intracellular signaling cascades, such as PI3K/cAMP pathways.5 These cascades can rapidly phosphorylate and activate transcription factors, leading to swift changes in gene expression or direct modulation of neuronal excitability and synaptic function.5 These rapid effects allow for dynamic modulation of neuronal activity and synaptic function.4 The existence of both classical genomic (slower, gene transcription) and rapid non-genomic (membrane-mediated, signaling cascades) actions of estrogen, mediated by distinct receptor subtypes, highlights the complexity and versatility of estrogen signaling in the brain. This mechanistic understanding is crucial for developing highly targeted therapeutic interventions, such as selective ER modulators, that can leverage specific pathways for neuroprotection while minimizing unwanted systemic side effects.

The neurobiological effects of estrogen are extensive and critical for optimal brain function:

• Modulation of Neural Differentiation, Proliferation, and Synaptic Plasticity: Estrogen plays a pivotal role in shaping brain circuitry. NDE2, for instance, is crucial for regulating synaptic plasticity, a fundamental process underlying learning and memory formation.2 Estrogen receptors in the brain participate in modulating neural differentiation, promoting neurogenesis (the birth of new neurons), and influencing the density and efficacy of synapses.4 These processes are all vital for cognitive resilience and adaptive brain remodeling throughout life.4
• Influence on Neurotransmitter Systems: E2 profoundly modulates various neurotransmitter systems, including the serotonergic, dopaminergic, and glutamatergic pathways.5 These systems are fundamental to diverse brain functions such as learning, memory, reward, mood regulation, and sexual behaviors.5 For example, E2 interacts with the dopaminergic system, which is implicated in cognitive aging and disorders like Parkinson's disease, where reductions in dopamine binding and receptors are observed.17
• Role in Neuroinflammation and Neuroprotection: Estrogen has potent neuroprotective properties, particularly against inflammatory insults within the central nervous system.4 It exerts significant anti-inflammatory effects, notably by modulating the activity of microglia, the brain's resident immune cells.9 Microglia are crucial for maintaining neuronal connectivity, clearing cellular debris, and responding to injury.9 However, prolonged or excessive inflammatory activation by microglia can be detrimental, contributing to neurodegenerative processes.9 Estrogen's ability to prevent and control inflammatory responses suggests a key role in protecting the brain from pathologies with an inflammatory component, such as Alzheimer's and Parkinson's diseases.9

Mechanisms of Androgen's Influence on Brain Function

Androgens, such as testosterone and dihydrotestosterone (DHT), are synthesized not only in the gonads and adrenal glands but also locally within the brain itself, functioning as neurosteroids.3 These hormones exert physiologically important effects on the structure and function of the central nervous system in both sexes.3 Androgen receptors (ARs) are widely expressed in numerous neuronal populations throughout the brain, including the neocortex, hippocampal formation, and amygdala.7

The androgen receptor (AR) is a type of nuclear receptor activated by binding to androgenic hormones like testosterone or DHT.6 Similar to estrogen receptors, ARs operate through both genomic and non-genomic mechanisms:

• Genomic Mechanisms: The primary mechanism of AR action involves the direct regulation of gene transcription.6 Upon steroid binding, the AR undergoes a conformational change, releases associated heat-shock proteins, and undergoes phosphorylation.6 The activated AR then translocates to the nucleus, where it dimerizes, binds to specific androgen responsive elements on DNA, and recruits coactivator proteins, leading to the transcription of target genes.6 This genomic pathway is fundamental for the development and maintenance of male sexual phenotype, but it also plays a crucial role in various other tissue types and physiological processes, including those in the brain.6
• Non-Genomic Mechanisms: Like estrogen receptors, ARs also mediate rapid, non-genomic actions.6 Recent studies have detected AR immunoreactivity in neuronal and glial processes, including axons, dendrites, and astrocytes, in regions such as the adult rat neocortex, hippocampal formation, and amygdala.7 This extranuclear localization suggests functional roles beyond nuclear transcription, enabling rapid modulation of neural activity. These extranuclear ARs may play an important role in the swift behavioral effects of androgens, allowing for more direct and immediate influences on neuronal function.7

Androgens contribute significantly to neuroplastic effects, particularly within the hippocampus, a brain region critical for learning and memory.3 These effects include synaptogenesis (the formation of new synapses) and the modulation of glial cell functions, which are essential for neuronal support and brain plasticity.3 Androgens also play a key role in the maintenance of male skeletal integrity via AR signaling in osteoblasts and osteocytes.6

While often considered "male hormones," androgens are critically important for women's health when present in balanced physiological concentrations.22 The AR is essential for normal female fertility, required for the development and full functionality of ovarian follicles and ovulation, through both intra-ovarian and neuroendocrine mechanisms.6 Androgens also play a role in regulating female sexual, somatic, and behavioral functions.6 However, when androgen levels are high and out of balance, a condition known as hyperandrogenism, they contribute to a range of hormonal, metabolic, reproductive, and psychological issues.22 Elevated androgens can have neurotoxic effects, and imbalances, such as those commonly observed in PCOS, are linked to cognitive decline.16 Androgens, like estrogens, operate through both genomic and non-genomic pathways, enabling both long-term structural changes and rapid modulation of neural activity. Furthermore, their role in the female brain is complex: essential for fertility and various functions at physiological levels, yet potentially neurotoxic at elevated levels, as seen in hyperandrogenism. This highlights the importance of hormonal balance rather than just presence or absence for optimal brain function.

The following table provides a comparative overview of the mechanisms through which estrogen and androgens influence brain function:

Table 2: Mechanisms of Estrogen and Androgen Action in the Brain

The Complex Interplay: Estrogen, Androgens, and Metabolic Factors in PCOS-Related Cognitive Changes

Polycystic Ovary Syndrome is characterized by a complex interplay of hormonal and metabolic dysregulations that collectively impact brain function. Hyperandrogenism, defined by elevated levels of androgens such as testosterone, is a hallmark feature of PCOS, affecting a significant majority (60-80%) of women with the condition.14 While androgens are essential for female health in balanced concentrations, excess levels can have neurotoxic effects.16 The direct impact of hyperandrogenism on brain function is suggested by findings that hyperandrogenic NIH-PCOS is associated with lower executive function performance.1 Indirectly, hyperandrogenism is intricately intertwined with insulin resistance, establishing a bidirectional relationship where elevated insulin can induce excess ovarian testosterone secretion, and high androgens can, in turn, contribute to metabolic dysfunction.14 This hormonal-metabolic feedback loop likely exacerbates cognitive vulnerabilities, creating a compounding effect on brain health.

The critical role of insulin resistance (IR) and subsequent hyperinsulinemia in PCOS-associated cognitive decline cannot be overstated. Insulin resistance is highly prevalent in PCOS, affecting 65-70% of women with the syndrome, often independent of obesity.13 Prolonged hyperinsulinemia has a direct negative effect on cognitive function by reducing the number of insulin receptors in the blood-brain barrier (BBB), thereby decreasing the transport of insulin into the brain.13 This impairment can lead to decreased brain glucose utilization, impacting neuronal energy metabolism, which is critical for learning, memory, and overall brain function.13 In severe cases, decreased brain glucose can even lead to seizures or irreversible brain damage.13 The exacerbation of executive function deficits observed in hyperandrogenic PCOS subjects with co-occurring insulin resistance underscores its central role in cognitive impairment within this population.1 The strong bidirectional relationship between insulin resistance and hyperandrogenism in PCOS creates a vicious cycle that profoundly impacts brain health. High insulin drives androgen production, and elevated androgens can worsen insulin sensitivity, leading to a compounding effect on brain glucose metabolism and overall neuronal function. This highlights metabolic dysfunction as a primary, modifiable driver of cognitive decline in PCOS.

Furthermore, PCOS is associated with a broader adverse cardiometabolic profile that extends beyond hyperandrogenism and insulin resistance.12 Chronic inflammation, dyslipidemia, and hypertension are common comorbidities that independently contribute to accelerated cognitive aging and adverse brain health outcomes.11 For example, hypertension can lead to vascular dementia by reducing blood flow to the brain.13 The cumulative burden of these interconnected metabolic and inflammatory factors likely contributes significantly to the observed cognitive deficits and white matter integrity changes in PCOS.11

The altered hormonal milieu in PCOS, involving not only elevated androgens but also potentially altered estrogen dynamics and often low progesterone levels, further contributes to observed cognitive and structural brain changes. While the primary focus is often on androgen excess, the neuroprotective effects of progesterone may be diminished when its levels are too low, as is common in PCOS.16 The overall hormonal imbalance, coupled with the pervasive metabolic dysfunction (insulin resistance) and chronic inflammation, creates a neurobiological environment conducive to cognitive impairment and structural brain changes, such as reduced white matter integrity.11 This complex interplay suggests a multi-hit hypothesis where various PCOS-related factors synergistically contribute to brain health compromise. While hyperandrogenism is a key feature of PCOS, the cognitive impact is likely not solely due to excess androgens but also the imbalance of other hormones, particularly the potential deficiency of neuroprotective progesterone. This suggests that a holistic view of the hormonal milieu, rather than focusing on a single hormone, is crucial for understanding and addressing PCOS-related brain health issues.

Broader Relevance: Estrogen's Enduring Impact on Brain Health Across the Lifespan

The study of PCOS and its impact on cognitive function provides valuable insights into the broader influence of sex hormones on brain health. Sex differences in cognitive functioning have been reported in both healthy individuals and those with disease, and these differences may be partly attributed to the modulating effects of sex hormones.20 While systematic advantages in overall executive function between sexes are not strongly supported by current evidence, individual components of executive functions can be modulated differently, often depending on the modality of testing.23 These differences extend to the vulnerability and manifestation of several psychiatric and neurological diseases, such as Alzheimer's disease (AD) and schizophrenia, highlighting the profound influence of sex hormones on brain health trajectories across the lifespan.4

As individuals age, circulating sex hormone levels naturally decrease, with a more rapid decline observed at menopause in women and a slower, more gradual reduction in men.4 The rapid decline of 17β-estradiol (E2) during the menopausal transition is associated with a number of changes in the brain, including cognitive alterations such as reduced verbal memory and processing speed, as well as effects on sleep and mood disturbances.17 This significant drop in estrogen levels entails a reduction in neuroprotection and resilience within the aging brain.4 Estrogen interactions have been implicated in the pathogenesis of various neuropsychiatric disorders, including AD, Parkinson's disease (PD), schizophrenia, and depression.4 The neuroprotective properties of E2, mediated through its diverse receptors, are essential for maintaining brain health, and their decline with aging contributes to age-related cognitive vulnerability and the observed sex differences in neurodegenerative disease incidence and progression.4

Recent research has introduced the compelling concept of "reproductive longevity," which posits a direct link between the duration of a woman's reproductive years—defined as the time between menarche (first menstruation) and menopause—and long-term cognitive health.18 Studies indicate that women who experience earlier menarche, later menopause, or a prolonged reproductive window exhibit signs indicative of slower brain aging.18 This discovery positions estradiol as a potential neuroprotective agent, with sustained elevated concentrations throughout the reproductive years appearing to play a crucial role in maintaining brain health and cognitive resilience.18 This concept underscores the cumulative neuroprotective benefits of endogenous estrogen exposure over a lifetime. The idea that the duration of physiological estrogen exposure over a woman's lifetime is intricately linked to long-term brain health and slower cognitive aging suggests that conditions like PCOS, which involve chronic hormonal dysregulation, or early menopause, might disrupt this protective trajectory, leading to an increased vulnerability to cognitive decline later in life.

Given the established neuroprotective roles of estrogen, the potential for hormonal therapies to combat neurodegeneration and preserve cognitive function is a significant area of ongoing research.4 Observational studies have pointed towards a decreased risk of AD and PD in women taking menopausal estrogenic replacement therapy (ERT), although results have varied, and the use of hormone therapy (HT) has been controversial due to concerns about breast cancer, thromboembolism, and stroke.8 However, a re-evaluation of older studies and the emergence of new data suggest that the benefits of HT can outweigh these risks, particularly when initiated early after menopause.8 Furthermore, certain formulations, such as ERT without progestins, may even be associated with a lower risk of breast cancer.8 The differential expression of estrogen receptor subtypes offers a promising avenue for more targeted therapeutic interventions. Specifically, ERβ is predominantly expressed in the brain, intestine, and gonads, making it a promising therapeutic target for neuroprotection while potentially avoiding the systemic side effects associated with widespread ERα activation.8 This understanding moves beyond broad hormonal replacement to a precision medicine approach, aiming to maximize brain benefits while minimizing systemic side effects. This paves the way for personalized or precision medicine approaches, where a better understanding of which individuals may particularly benefit from such treatment is critical for preventing or treating cognitive disturbances during aging.4

Conclusion and Future Directions

Polycystic Ovary Syndrome is not merely a reproductive disorder but a complex neuroendocrine condition with significant implications for brain health and cognitive function. The evidence consistently demonstrates that hyperandrogenism and insulin resistance, central features of PCOS, are strongly associated with specific cognitive deficits, particularly in executive functions, and structural brain changes like reduced white matter integrity, even from young adulthood.1 These impacts are mediated by the multifaceted actions of sex hormones like estrogen and androgens, which act as neurosteroids influencing neurogenesis, synaptic plasticity, neurotransmitter systems, and neuroinflammation through both genomic and non-genomic pathways.2 The broader context reveals that lifetime estrogen exposure contributes significantly to cognitive longevity, and its decline with aging can increase vulnerability to neurodegenerative diseases.18 The insights gained from studying PCOS, a condition characterized by chronic hormonal and metabolic dysregulation, serve as a valuable model for understanding the broader impact of sex hormones on brain health, aging, and vulnerability to neurodegenerative diseases. The findings from PCOS can inform research and interventions for other conditions involving hormonal imbalances or metabolic dysfunction.

Despite significant progress, there remains a critical need for additional research to confirm these findings in larger, more diverse cohorts and to further investigate the precise mechanistic pathways linking PCOS to cognitive outcomes.1 Future studies should focus on:

• Detailed Mechanistic Investigations: Elucidating the specific molecular and cellular mechanisms by which altered androgen and insulin signaling, as well as chronic inflammation, translate into neuronal dysfunction and structural brain changes in PCOS. This includes exploring the reversal of normal brain microstructure-hormone relationships observed in PCOS.15
• Longitudinal Studies: Continuing to track cognitive trajectories and brain changes in PCOS populations over extended periods, from adolescence through post-menopause, to better understand the progression and long-term consequences of the condition.
• Identification of Modifiable Factors: Pinpointing specific modifiable factors within the complex PCOS phenotype that, when targeted, can most effectively mitigate cognitive decline.
• Hormone Quantification and Biomarkers: Future research should incorporate precise hormone quantification and biomarkers of inflammation, neurodegeneration, and vascular health to refine understanding of estradiol's specific contribution and its interplay with other physiological systems affecting brain health.18
• Neurodevelopmental Impacts: Further investigating the potential intergenerational effects of PCOS, particularly the impact of in utero androgen exposure on offspring neurodevelopmental outcomes like autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD).19

The strong links between PCOS, insulin resistance, and cognitive decline highlight the importance of early and sustained management of metabolic health for preserving brain function.13 The multi-faceted nature of PCOS's impact on the brain, involving hormonal, metabolic, inflammatory, and even mental health components, necessitates a holistic and personalized approach to patient management. This goes beyond addressing individual symptoms to targeting the underlying systemic dysregulations to preserve long-term cognitive health.

Potential therapeutic and lifestyle interventions for improving cognitive outcomes in PCOS and broader brain health include:

• Lifestyle Interventions: Weight management, adopting a nutrient-rich diet (e.g., fiber-filled diets to reduce insulin resistance), and engaging in regular exercise are crucial first-line interventions.13 These strategies can significantly improve insulin sensitivity, enhance blood flow to the brain, and positively impact mental health (e.g., reducing depression), thereby mitigating cognitive risks.13
• Pharmacological Approaches: While conventional treatments for PCOS often include metformin for insulin resistance and oral contraceptives for hormonal regulation 22, future therapeutic strategies might involve more targeted approaches, such as selective estrogen receptor modulators (SERMs) that specifically activate neuroprotective pathways without broad systemic effects.8
• Cognitive Enrichment: Promoting cognitive enrichment activities, such as reading, engaging in mentally stimulating games, and memory training, can also contribute to preserving mental function and overall brain health in individuals with PCOS.16

These integrated strategies underscore the evolving understanding of PCOS as a condition requiring comprehensive management that extends beyond reproductive health to encompass long-term neurological and cognitive well-being.

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