Neuropsychiatric and cognitive manifestations of endometriosis: insights into the ‘endometriosis brain’

Downloads 1,758 Views 5,901 Citations 1 Citations are sourced from Dimensions and calculated once a day. MLA Alexander, Kyle G., et al. “Neuropsychiatric and Cognitive Manifestations of Endometriosis: Insights into the ‘Endometriosis Brain.’” Academia Mental Health and Well-Being, vol. 2, no. 4, Academia.edu Journals, 2025, doi:10.20935/MHealthWellB7938. APA Alexander, K. G., Nordahl, E. J. B., Newton, T. I. J., & Georgiou, C. (2025). Neuropsychiatric and cognitive manifestations of endometriosis: insights into the ‘endometriosis brain.’ Academia Mental Health and Well-Being, 2(4). https://doi.org/10.20935/MHealthWellB7938 Chicago Alexander, Kyle G., Emma J. B. Nordahl, Toby I. J. Newton, and Christos Georgiou. “Neuropsychiatric and Cognitive Manifestations of Endometriosis: Insights into the ‘Endometriosis Brain.’” Academia Mental Health and Well-Being 2, no. 4 (2025). doi:10.20935/MHealthWellB7938. Vancouver Alexander KG, Nordahl EJB, Newton TIJ, Georgiou C. Neuropsychiatric and cognitive manifestations of endometriosis: insights into the ‘endometriosis brain.’ Academia Mental Health and Well-Being. 2025;2(4). doi:10.20935/MHealthWellB7938 Harvard Alexander, K. G. et al. (2025) “Neuropsychiatric and cognitive manifestations of endometriosis: insights into the ‘endometriosis brain,’” Academia Mental Health and Well-Being. Academia.edu Journals, 2(4). doi: 10.20935/MHealthWellB7938. Received 1 May 2025 Accepted 28 September 2025 Published 31 October 2025 This review explores the multifaceted impact of endometriosis on women’s health, emphasizing its association with neuropathic pain, cognitive dysfunction, migraine, mental health disorders, and reduced quality of life. Central sensitization plays a crucial role in the persistence and severity of neuropathic pain in endometriosis, driven by glial activation, neuroplasticity, and microbial dysbiosis, often leading to heightened pain sensitivity beyond ectopic tissue presence. Cognitive impairments, characterized as “brain fog”, involve disrupted brain connectivity, neuroinflammation, and hormonal imbalances, contributing to daily functional challenges. The coexistence of migraine exacerbates disease burden, sharing inflammatory pathways and hormonal sensitivities, yet remains under-treated. Anxiety and depression are prevalent, mediated by neuroinflammatory processes, chronic pain, and psychosocial stressors, significantly impairing mental health and social functioning. Furthermore, endometriosis substantially decreases quality of life across physical, emotional, and social domains, often surpassing other chronic conditions. Despite the complex symptomatology, current management strategies require a multidisciplinary approach, integrating pain control, mental health support, and personalized therapies to improve overall outcomes. Recognizing and addressing these interconnected aspects is essential for advancing patient care and enhancing quality of life for women affected by endometriosis. Endometriosis (EM) is a complex, chronic inflammatory condition in which endometrial-like tissue grows outside the uterus, most commonly affecting the peritoneum, ovaries, and deep pelvic structures such as the rectovaginal septum and bowel [1–4]. It is estimated to affect 10–15% of women of reproductive age, with the highest prevalence seen between ages 25 and 45 [2, 3]. The condition frequently presents with pelvic pain, dysmenorrhea, dyspareunia, and in many cases, infertility [1, 5–7]. Chronic pelvic pain (CPP) can significantly impair quality of life and may persist despite lesion removal or suppression therapy. Management of EM typically involves a combination of hormonal therapies and surgical interventions. First-line treatments include combined oral contraceptives and progestins, with gonadotropin-releasing hormone (GnRH) analogs often reserved for refractory cases [8–10]. However, while these approaches target peripheral lesions and hormonal pathways, they do not fully address the broader neuropsychological burden of the disease. Emerging evidence highlights a significant overlap between EM and neurological or neuropsychiatric symptoms. Women with EM are more likely to experience mood disorders, cognitive disturbances, and headaches, raising questions about how chronic pelvic pain and systemic inflammation affect the central nervous system (CNS) [11–13]. The colloquial term “endometriosis brain” has been used to describe these cognitive and affective changes, which may be linked to structural and functional alterations in the brain [14]. Persistent pain after lesion removal has further prompted investigation into CNS sensitization as a potential mechanism [15]. In this review, we explore the interplay between endometriosis and the CNS. We aim to synthesize current findings on the neuropsychiatric manifestations of EM, examine potential pathophysiological mechanisms, and discuss implications for clinical management. A comprehensive literature search was undertaken across major academic databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering the period from 1997 to 2024. The search strategy utilized a combination of Medical Subject Headings (MeSH) and free-text keywords, including, but not limited to, the following: “endometriosis”, “neuropathic pain”, “central sensitisation”, “cognitive dysfunction”, “brain fog”, “migraine”, “anxiety”, “depression”, “mental health”, “quality of life”, “neuroinflammation”, “glial activation”, “HPA axis”, “gut microbiome”, and “multidisciplinary management.” Boolean operators (“AND”, “OR”) were employed to optimize search sensitivity and specificity. Filters were applied to limit results to English-language publications. Inclusion criteria encompassed original research articles, systematic reviews, meta-analyses, cohort studies, and case–control studies that explored the neurological, neuropsychiatric, or psychosocial dimensions of endometriosis. Special attention was given to studies investigating potential pathophysiological links between endometriosis and central nervous system (CNS) function or dysfunction. Excluded from the review were editorials, opinion pieces, letters to the editor, non-peer-reviewed sources, and studies solely focused on the gynecological or reproductive aspects of endometriosis without reference to neurological, cognitive, or mental health outcomes. Articles lacking accessible full-text versions were also excluded. As this is a narrative review, not all studies meeting the inclusion criteria were incorporated. Instead, we selectively included those that were most relevant and informative in shaping the conceptual framework and advancing the overarching narrative on the intersection of endometriosis and neuropsychiatric manifestations. All included studies were assessed qualitatively for scientific rigor, methodological transparency, sample size, and relevance to the review objectives. As this review is based solely on previously published data, ethical approval and informed consent were not required. Central sensitization describes a maladaptive response of the CNS, in which pain processing becomes dysregulated, leading to an exaggerated response to stimuli that are typically non-painful or only mildly painful [16–18]. This abnormal processing results in persistent, often severe pain that is disproportionate to the initial inflammatory stimulus—a hallmark feature of neuropathic pain. In the context of EM, central sensitization has gained recognition as a key contributor to chronic pain that persists even after the removal of ectopic endometrial tissue [19]. Common neuropathic symptoms include burning, shooting, or electric-shock-like sensations, along with allodynia and hyperalgesia [20, 21]. The exact mechanisms underlying neuropathic pain in EM are still not fully understood, but current research points to several key processes. Studies using animal models have shown that both central and peripheral sensitization contribute to persistent pain [22–24]. One prominent theory involves glial cells becoming activated and releasing inflammatory signals. Bashir et al. demonstrated that in mice with EM, microglia (a type of glial cell) in various brain regions become more active, which correlates to increased inflammatory markers [22]. This glial activation is believed to amplify pain signals, creating a heightened pain response. In addition to glial involvement, neuroplasticity—the brain’s ability to reorganize itself—also plays a role. EM appears to induce changes in neural circuitry through both central and peripheral pathways, which may explain the development of CPP even after the initial tissue lesions are removed [23]. Recently, researchers have also highlighted the role of microbial dysbiosis—an imbalance in gut bacteria—in EM-related inflammation. This dysbiosis can worsen systemic inflammation, potentially fueling ongoing pain and other symptoms [24, 25]. In a large cross-sectional study involving over 1,400 women with EM, 40% met the criteria for neuropathic pain based on the validated painDETECT screening tool, while an additional 35% exhibited a mixture of neuropathic and nociceptive features [26]. These findings suggest that more than two-thirds of women with EM experience pain that is, at least in part, mediated by alterations in CNS processing, rather than solely peripheral tissue damage. Importantly, the presence of neuropathic pain does not just mirror disease severity. Instead, it correlates with longer pain duration, increased psychological distress, and a higher likelihood of multiple surgical interventions [26]. EM patients with neuropathic pain frequently report higher levels of cognitive dysfunction—such as memory lapses and difficulties with concentration—and emotional exhaustion, highlighting the interplay between physical pain and mental health [26]. Moreover, women who have undergone recurrent abdominal surgeries are significantly more likely to report neuropathic features. This suggests a potential causal relationship where tissue injury from multiple procedures contributes to persistent alterations in pain processing pathways, further worsening neuropathic symptoms [24]. A multimodal approach is increasingly advocated, combining pharmacological and non-pharmacological interventions. Pharmacologically, options include serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and anticonvulsants like pregabalin and gabapentin—agents known to modulate neural hyperexcitability [27]. These medications aim to dampen abnormal pain processing pathways and reduce neuropathic symptoms. Non-pharmacological strategies also play a vital role. Cognitive-behavioral therapy (CBT), physiotherapy, and neuropathic pain education have demonstrated promising results in reducing symptom burden and improving quality of life (QoL) [27, 28]. These approaches help patients develop coping skills, modify pain perception, and address psychological factors intertwined with chronic pain. Surgical intervention, typically lesion excision, has been associated with reductions in neuropathic symptoms in some cases, particularly when combined with other treatments [29]. Early identification of central sensitization features—such as allodynia, hyperalgesia, or pain disproportionate to tissue damage—is crucial. Referral to multidisciplinary pain management teams, including neurologists, pain specialists, and mental health professionals, is essential for optimizing outcomes in this patient population. Although EM is predominantly recognized as a gynecological and pelvic pain disorder, emerging neuroimaging data and patient reports indicate a broader impact on cognitive function. Many women describe their experience as “brain fog”, a subjective term encompassing a spectrum of neurocognitive difficulties—such as memory lapses, impaired attention, slowed processing, and reduced executive functioning [30, 31]. While direct, large-scale evidence linking EM to cognitive impairment remains limited, clinical observations consistently reveal that a high proportion of women report persistent cognitive difficulties, underscoring the need for further investigation into this aspect of the disorder [32, 33]. The mechanisms underlying cognitive impairment in EM are multifactorial, involving complex interactions between persistent pain, hormonal fluctuations, and neuroinflammatory processes. Although direct neurobiological evidence remains limited, data from neuroimaging and clinical studies suggest several key pathways. One prominent hypothesis centers on disrupted connectivity within brain networks responsible for pain regulation and cognitive control. Neuroimaging has revealed altered functional connectivity, particularly between the right anterior insula—an area implicated in integrating sensory and affective components of pain—and regions involved in executive functions, such as the middle frontal gyrus and cerebellum [34]. These disruptions may manifest as attentional deficits, mental fatigue, and reduced cognitive flexibility, all characteristic features of “brain fog”. Additionally, structural changes have been observed, including increased gray matter volume (GMV) in regions such as the lingual gyrus, calcarine gyrus, and cerebellum in women with EM [35]. More severe dysmenorrhoea was linked to increased GMV in the left inferior parietal lobule, while depressive symptoms were associated with reduced GMV in the right superior medial gyrus [35]. Meanwhile, dyspareunia correlated with reduced cortical thickness in the left inferior and middle temporal gyri [35]. These neuroanatomical alterations may reflect neuroplastic adaptations or maladaptations related to chronic pain and stress. Chronic pain can also dysregulate the hypothalamic–pituitary–adrenal (HPA) axis, leading to elevated cortisol levels. Excess cortisol has neurotoxic effects, impairing hippocampal function and neurogenesis, which further compromises cognition [30]. Moreover, neuroinflammation, driven by glial activation, may interfere with synaptic transmission and neuroplasticity, impairing cognitive processes [36]. Self-reported data indicate that a considerable proportion of women with EM perceive significant impairment in cognitive functioning. Many describe symptoms such as forgetfulness, difficulty concentrating, mental fatigue, and slowed processing speed—collectively often referred to as “brain fog”—which can interfere with daily activities, work performance, and social interactions [32]. Although objective neuropsychological assessments, in some studies, demonstrate neurophysiological alterations in EM patients, there were no marked deficits in standardized cognitive testing [34, 37]. This discrepancy may reflect compensatory neural mechanisms or limitations in the sensitivity of certain cognitive testing tools. Currently, there are no specific pharmacological treatments targeting cognitive impairment in EM. Management should focus on mitigating contributing factors such as pain, stress, and inflammation [38]. Effective pain control—via pharmacological agents, physical therapy, and lifestyle modifications—can indirectly improve cognitive symptoms by reducing neuroinflammation and stress responses. Psychological support, including CBT, stress management, and sleep optimization, plays a crucial role in addressing mental health and cognitive clarity. Migraine is a chronic and often disabling neurological disorder characterized by recurrent episodes of moderate to severe headache, commonly accompanied by nausea, photophobia, and phonophobia [39]. Among women with EM, migraine appears with significantly higher frequency than in the general population [40–42], specifically migraine without aura, compared to migraine with aura [43]. Shared biological pathways, including inflammation, hormonal fluctuations, and neuropeptide dysregulation, underpin the connection between EM and migraine [44]. Both conditions show elevated expression of inflammatory genes, such as those in the TNF-α and PI3K-Akt-mTOR pathways, indicating common inflammatory mechanisms [45]. Genetic studies also suggest shared susceptibility factors [46]. In women of reproductive age, migraine susceptibility is strongly linked to hormonal changes, especially estrogen fluctuations. Aberrant estrogen levels in EM can heighten sensitivity to hormonal shifts, with estrogen withdrawal often acting as a migraine trigger [47, 48]. Elevated prolactin levels may also sensitize trigeminal afferents, increasing attack risk [49]. Additionally, calcitonin gene-related peptide (CGRP), a neuropeptide central to migraine pathogenesis, is increasingly recognized in EM-related inflammation [50]. Elevated CGRP levels may perpetuate inflammation and pain cycles, intensifying symptoms in patients with both conditions. When migraine co-occurs with EM, the disease trajectory tends to worsen. Recent studies show women with both conditions report higher migraine-related disability scores, increased attack frequency, and greater functional impairment compared to those with migraine alone [51]. They also experience a significant reduction in QoL, with more missed workdays and social engagements, reflecting the compounded burden of two chronic pain conditions [52]. Migraine incidence is notably higher in certain EM patient subgroups. For example, migraine without aura is more prevalent in advanced EM stages and patients with concomitant adenomyosis [53]. Additionally, symptoms such as dysmenorrhea and dysuria are more common in women with both EM and migraine than in those without migraine [54]. Despite the high prevalence and impact, migraine treatment in women with EM is often underutilized. A recent study found that only about 8% of women with both conditions used triptans, the first-line acute migraine medication [55]. Many rely on over-the-counter analgesics or hormonal therapies, which may be insufficient for managing the migraine burden [56]. In cases of migraine with aura, COCs are generally contraindicated due to increased stroke risk [57]. However, for women with migraine without aura, who are non-smokers and under 35 years old, COCs may be considered, especially if EM symptoms warrant hormonal treatment [58]. It is important to note that COCs can sometimes exacerbate migraine symptoms, but the effects are typically small and depend on the specific regimen [59]. Further research is needed to evaluate continuous COC therapy or progestin-only options, in EM patients with migraine, as evidence remains limited. Generalized anxiety disorder (GAD) is a prevalent mental health condition marked by persistent and excessive worry that is difficult to control [60]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), it must occur more days than not for at least six months and be accompanied by symptoms such as restlessness, fatigue, irritability, sleep disturbances, and difficulty concentrating [60]. In women with EM, GAD appears significantly more frequently than in the general population [61, 62]. Major Depressive Disorder (MDD) is another mental health condition frequently reported among women with EM [63]. It is characterized by persistent low mood, hopelessness, and a loss of interest in previously enjoyable activities, often accompanied by fatigue, guilt, and cognitive dysfunction [60]. There is no consensus regarding why patients with EM are more likely to experience anxiety and depression; however, neurotransmitter dysregulation is likely to play a role [24, 64]. Similar to the mechanisms underlying neuropathic pain and cognitive dysfunction, patients with CPP experience neuroinflammation, secondary to inflammatory cytokines crossing the blood–brain barrier. In patients with anxiety or depressive symptoms, such inflammation likely disrupts neurotransmitters involved in mood regulation [64]. Additional factors include microbial dysbiosis, oxidative stress, and reduced levels of brain-derived neurotrophic factor (BDNF), all linked to psychological symptoms in EM patients [25]. It is also important to recognize that living with chronic pain and other symptoms of EM can directly impact mental health [25, 35, 65]. Studies show that rates of psychological disorders are similar between women with EM and those with pelvic pain from other causes [66]. For example, symptoms like sexual dysfunction and dyspareunia can negatively affect social interactions and relationships [36], contributing to anxiety and depression. Overall, the interconnected nature of these physiological and psychological factors explains the heightened mental health risks among individuals with EM. Clinically significant anxiety symptoms are reported in approximately 11.5% to 87.5% of women with EM, particularly among those with severe pain, longer diagnostic delays, or concerns about infertility [63, 67]. A study by Armour et al. (2019) found that women with frequent flare-ups were nearly twice as likely to meet criteria for GAD, especially if they felt little control over their treatment [68]. Qualitative data highlights feelings of being dismissed by healthcare providers, fear of disease progression, and social isolation. One participant described her experience as “the most lonely condition I can imagine”, emphasizing her anxiety [69]. Regarding depression, prevalence rates among women with EM range widely from 9.8% to 98.5% [63], with rates closely linked to pain severity [70]. Specific symptoms of depression—such as pessimism, social withdrawal, negative self-image, fatigue, feelings of worthlessness, and decreased sexual desire—are also strongly associated with EM [71, 72]. A large longitudinal study by Della Corte (2020) found that women who waited over seven years for a diagnosis reported significantly higher rates of depressive symptoms and suicidal ideation than those diagnosed earlier [73]. This suggests that depression in EM patients is not solely a reaction to pain but is also caused by the emotional toll of delayed diagnosis and disrupted daily life. While treatments like laparoscopic surgery and hormonal suppression can reduce pain and sometimes alleviate anxiety, most studies indicate that dedicated mental health support is essential [27]. Interventions such as CBT, mindfulness-based stress reduction, and anxiolytic medications have demonstrated benefits when incorporated into EM care [27]. Clinicians should routinely screen for anxiety symptoms, especially in patients with severe pain, infertility concerns, or a history of trauma, and consider early referral to mental health services as part of a comprehensive management plan [74]. Depression often persists even after surgical or hormonal treatments, particularly when expectations for symptom relief are unmet [73]. This underscores the need for ongoing psychological support beyond standard EM therapies. If pharmacological treatment is necessary, SSRIs or SNRIs are preferred [75]. Additionally, therapies like CBT, mindfulness, and relaxation techniques can help patients manage chronic pain, improve mental health, and enhance QoL [76]. Regular depression screening with tools such as the Patient Health Questionnaire-9 (PHQ-9), along with access to mental health services and interdisciplinary care pathways, are crucial for better long-term outcomes [77]. Addressing the psychosocial impact of EM through fertility counseling, peer support groups, and trauma-informed care can further support patients’ emotional well-being [78]. QoL encompasses an individual’s overall well-being, including physical, emotional, and social aspects [79]. Using the Short Form Health Survey (SF-36) QoL assessment tool, studies have demonstrated that women with EM report significantly lower scores across all evaluated domains, such as physical function, role limitations, bodily pain, general health, vitality, and social functioning [67]. In particular, pain symptoms—such as dysmenorrhea, dyspareunia, painful defecation and CPP—emerged as the primary drivers for this decline in health-related QoL, more so than decline in fertility and disease stage [67]. Additionally, psychosocial factors—like anxiety, sleep issues, fatigue and depression—also substantially contribute to reduced QoL, with complex interrelations across emotional, functional and social domains [67]. This not only highlights the areas of life that are most impacted by EM, but also where treatment plans should target to reduce the burden of EM the most. The impact of EM on QoL is so substantial that it often exceeds the burden experienced by individuals with conditions such as heart disease, diabetes, and breast cancer [80]. Research on other reproductive disorders in women similarly shows an overall impairment in health-related QoL [81–83]. Specifically, conditions associated with pelvic pain and CPP are linked to a greater reduction in QoL [81]. A common finding across studies assessing QoL in women with reproductive disorders is that the causes are typically multifactorial. These include felt and experienced stigma, chronic pain, fatigue, and unmet psychosocial needs [81–83]. Studies comparing patients before and after surgical excision of EM lesions have shown substantial improvements in QoL symptoms [84], specifically symptoms relating to sexual function and pain [85]. Oral GnRH antagonists, such as Elagolix, Relugolix, and Linzagolix, have demonstrated significant potential to improve key aspects of QoL, especially reducing physical pain and enhancing functional ability [86, 87]. Given the wide range of QoL domains impacted in patients with EM, various combinations of these treatments are often employed. Primary care clinicians and gynecologists should be equipped to identify and manage neurological symptoms associated with endometriosis; a concise overview of which, is provided in Figure 1. Managing such patients requires a holistic, patient-centered approach that emphasizes early recognition, multidisciplinary collaboration, and individualized care. The interplay between hormonal, neurological, and psychological factors is complex in EM, therefore clinicians should adopt a comprehensive assessment strategy that includes routine neurological screening, mental health evaluation, and detailed history-taking to identify central sensitization, mood disturbances, headache and cognitive symptoms. A key component of management involves educating both patients and healthcare providers about the bidirectional impact of EM and neuropsychological symptoms. This can help foster a collaborative therapeutic relationship and ultimately improve treatment adherence. Clinicians should refer patients to appropriate mental health services, including psychological support, CBT, and stress management techniques. Pharmacological interventions should be tailored to address specific symptoms—ranging from hormonal modulators and analgesics to antidepressants, anticonvulsants, and mood stabilizers—which are highlighted in the aforementioned sections. Multidisciplinary referrals—including pain specialists, neurologists, psychologists, and reproductive health experts—are also vital for improving QoL and addressing the complex manifestations of EM on the brain and overall well-being. A deeper understanding of the neurological manifestations of endometriosis will require targeted research efforts. Large, well-designed cohort studies are needed to quantify the prevalence and severity of symptoms such as neuropathic pain, cognitive dysfunction, anxiety, and depression in women with EM. Beyond documenting symptom burden, such studies can help define clinical subtypes and guide more tailored interventions. Equally important is mechanistic research into the biological underpinnings of these symptoms. Investigations into neuroinflammation, hormonal dysregulation, and the role of gut–brain axis disturbances may reveal novel therapeutic targets and clarify how peripheral disease contributes to central symptoms. RCTs assessing the efficacy of pharmacologic and non-pharmacologic treatments for neurologic and psychiatric symptoms in EM are also urgently needed. For example, trials focusing on neuropathic pain agents, migraine therapies, or antidepressants may offer practical guidance for symptom management in this population. Finally, detailed case reports and series remain valuable. These narratives can illuminate the variability and complexity of patient experiences, highlighting symptom patterns and treatment responses that large studies may overlook. Integrating patient-reported outcomes into future research will ensure that management strategies remain both evidence-based and patient-centered. The authors used AI language models (Grammarly and Scribbr) for linguistic editing (grammar, syntax, and sentence restructuring) to improve readability. The AI did not contribute to study design, data extraction, thematic synthesis, or interpretation of findings. All content related to study selection, data synthesis, and conclusions was produced by the authors after critical appraisal and verification. The authors fully support Academia.edu Journals’ adherence to COPE's position statement regarding the use of AI tools in manuscript preparation and confirm that this use has been managed responsibly and ethically. Conceptualization, K.G.A.; writing—original draft preparation, K.G.A., E.J.B.N., T.I.J.N., C.G.; writing—review and editing, K.G.A., E.J.B.N., T.I.J.N., C.G.; supervision, K.G.A. All authors have read and agreed to the published version of the manuscript. Academia.edu Journals stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. 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