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Fluoride has come under recent scrutiny regarding concerns over potential neurodevelopmental and endocrine-related toxicities, with recent reviews by the National Toxicology Program (NTP) and European Food Safety Authority (EFSA) concluding with moderate or reasonable confidence, respectively, that exposure to drinking water having greater than 1.5 mg fluoride/L is associated with lower IQ in children. A key outcome of these reviews is the uncertainty regarding the biological plausibility of these findings. However, it has been hypothesized that endocrine disruption could be a potential factor. To determine if sodium fluoride exerts direct biological activity on molecular and cellular targets related to endocrine disruption, receptor binding and activity assays of thyroid and other hormone-related targets, H295R steroidogenesis, and sodium-iodide symporter (NIS) assays were carried out using exposures comparable to or in excess of those that have been reported to be associated with neurodevelopmental outcomes and other effects. Sodium fluoride at up to 316 μM NaF did not affect synthesis of estrogen or testosterone. Sodium fluoride at up to 10 μM NaF did not interact with aromatase, steroid 5 alpha-reductase, estrogen receptors, androgen receptors, thyroid hormone receptors, nor did it inhibit thyroid peroxidase. Furthermore, there were no changes in iodide uptake via symporter transport (up to 300 μM NaF). Other endocrine targets were also evaluated at 10 μM NaF, including PR, PPARα, PPARγ, AhR, CAR, PXR, RARα, or GR, and no binding was observed either. Together, the results from this series of experiments demonstrate an absence of effects of fluoride on endocrine disruption targets at concentrations comparable to or in excess of exposures reported in the literature to be associated with neurodevelopmental outcomes and other effects.
Hyperprolactinemia, characterized by persistently elevated serum prolactin levels, is traditionally associated with reproductive and metabolic disturbances. Emerging evidence now implicates hyperprolactinemia in central nervous system dysfunction, particularly in the pathogenesis of neurodegenerative disorders. Chronic elevation of prolactin has been linked to tau pathology, a hallmark of Alzheimer's disease and related tauopathies, through mechanisms that promote tau hyperphosphorylation, microtubule destabilization, and neuronal compromise. This systematic review assesses the evidence on hyperprolactinemia and tau pathology. The overall literature search was performed in PubMed, Scopus, and Web of Science with the help of certain keywords that included prolactin, tau protein, neuroinflammation, oxidative stress, and dopaminergic signaling. The studies were narrowed down to a set of pre-established inclusion and exclusion criteria (original research, molecular and clinical data, relevance to neuropsychiatric disorders, non-English articles, reviews, animal studies that did not have a translational relevance). A clear study selection procedure was used, with independent screening and consensus-based resolution. The results generalize molecular, transcriptomic, neuroimaging, and clinical data to assess mechanistic connections and treatment prospects. Neurons susceptible to tau accumulation under hyperprolactinemic states exhibit altered apoptotic signaling, impaired vesicular trafficking, and mitochondrial dysfunction. These disruptions correlate with increased neuroinflammation and oxidative stress, suggesting a mechanistic link between endocrine imbalance and tau-mediated neurotoxicity. Therapeutic agents such as dopamine agonists, selective kinase inhibitors, and prolactin receptor antagonists have the potential to restore neuroendocrine homeostasis and mitigate tau pathology. The findings underscore hyperprolactinemia as a modifiable risk factor for cognitive decline. The neuroendocrine-tau axis represents a critical interface where hormonal dysregulation may precipitate neurodegenerative cascades. Clinical implications in the manuscript include that prolactin may serve as a biomarker of an early neurodegenerative process and that its role in the treatment approach includes dopamine agonists, prolactin receptor antagonists, and kinase inhibitors. This simplified methodology will ensure the highlights are original and have translational implications beyond mere abstract repetition. Hyperprolactinemia-induced tau dysregulation presents novel opportunities for neuroprotective targeting. By bridging molecular mechanisms with clinical relevance, this review advocates for longitudinal studies to assess cognitive outcomes in hyperprolactinemic individuals. Emphasizing endocrine health may enhance cognitive resilience and inform future strategies for diagnosis, risk stratification, and therapeutic intervention in neurodegenerative diseases.
Endocrine therapy is a fundamental treatment for hormone receptor-positive breast cancer. However, treatment-related symptoms may lead to poor adherence and premature discontinuation, adversely affecting clinical outcomes. eHealth technology interventions have been widely applied as potential tools to support patient education, symptom management, and adherence. This review aimed to evaluate the application, effectiveness, and limitations of eHealth technologies in symptom management among patients with breast cancer undergoing endocrine therapy. A systematic literature search was conducted across 9 databases, including MEDLINE Complete, Academic Search Complete, PubMed, and CINAHL Ultimate, covering studies published between February 2015 and February 2025. Keywords included "breast cancer," "endocrine therapy," and "ehealth," along with synonyms and related terms. Eligible studies examined the use of eHealth interventions in patients with breast cancer undergoing endocrine therapy. From 1352 records, 30 (2.2%) studies were included after screening and full-text review. The 30 included studies comprised 13 (43.3%) randomized controlled trials, 7 (23.3%) single-arm studies, 3 (10%) retrospective analyses, 2 (6.7%) observational studies, 3 (10%) mixed methods studies, and 2 (6.7%) qualitative studies. eHealth interventions, primarily mobile apps, telemonitoring systems, and SMS text messaging, demonstrated benefits in short-term symptom management, such as reductions in hot flashes, joint pain, anxiety, and sexual distress and improved medication adherence. However, evidence regarding long-term adherence and quality of life outcomes remains inconsistent. Considerable heterogeneity existed in study designs, adherence measures, and intervention components. Nurses were considered key contributors in implementing and monitoring eHealth interventions. eHealth interventions show promise in improving symptom management and short-term adherence among patients with breast cancer receiving endocrine therapy. Methodological limitations and variability across studies restrict the strength of conclusions. Future research should prioritize long-term outcomes, standardized measures, and integration into routine clinical practice while incorporating perspectives from multiple stakeholders.
In medicine, nomenclature shapes diagnostic reasoning, clinical pathways, research priorities, and patients' understanding of their condition. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, affecting one in eight women and more than 170 million individuals worldwide, has long carried a name that foregrounds ovarian morphology and implies pathological cysts. This framing has narrowed clinical attention, contributed to delayed diagnosis in up to 70% of affected individuals, and obscured the broader endocrine, metabolic, psychological, and cardiometabolic dimensions of the syndrome. A recent global consensus process led by the Global Name Change Consortium, involving 56 organizations, patients, clinicians, and researchers, has renamed the condition polyendocrine metabolic ovarian syndrome (PMOS). The new terminology recognizes interacting disturbances in androgen production, insulin signaling, neuroendocrine regulation, and ovarian function, while centering metabolic features such as insulin resistance, dysglycemia, dyslipidemia, cardiovascular risk, and metabolic dysfunction-associated steatotic liver disease. This editorial examines the historical evolution of diagnostic criteria from the 1990 NIH criteria through the 2003 Rotterdam consensus to the 2023 International Evidence-Based Guideline, reviews the structured renaming process, and draws parallels with the transition from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD). It discusses controversies surrounding the new name, implementation challenges, and the infrastructure needed to ensure that PMOS improves diagnostic accuracy, broadens multidisciplinary care, and reduces stigma without compromising the existing evidence base.
Unconscious/implicit processes are increasingly conceptualized as biologically instantiated, multisystem regulatory functions rather than purely psychological constructs. This review examines whether an integrative framework linking psychoneuroimmuneendocrine (PINE) regulation, epigenetic mechanisms, and principles of morphogenetic organization can help organize evidence relevant to "unconscious ontogenesis." To systematically review empirical evidence on PINE-related regulation and epigenetic modifications associated with unconscious/implicit processing, and to evaluate developmental morphogenetic principles as an organizing conceptual template (distinct from direct evidence of adult unconscious processing). We searched PubMed/MEDLINE, Web of Science, and Scopus (1990-2024), plus gray literature sources, for experimental and observational studies, systematic reviews/meta-analyses, and a limited set of theoretical/historical works used only for conceptual context. Unconscious/implicit processing was operationalized as outcomes measured with implicit or non-conscious paradigms (behavioral tasks) and/or biological proxies of automatic regulation (e.g., autonomic, endocrine, immune, epigenetic, or neuroimaging markers) when the study design or authors' framework explicitly linked these measures to implicit/unconscious processing. Risk of bias was assessed with RoB 2, ROBINS-I, Newcastle-Ottawa Scale, and GRADE as appropriate; theoretical works were excluded from quantitative synthesis and bias assessment. No language restrictions were applied at the search stage; non-English studies were screened via available abstracts and full texts were used when accessible. From 1,245 records identified, 58 studies met inclusion criteria; 30 contributed to the quantitative synthesis. Evidence most consistently supported associations between PINE-system dysregulation and stress-adaptive behavioral/physiological outcomes, as well as between environmental exposures and epigenetic modifications relevant to neurodevelopment and stress regulation. In contrast, morphogenetic fields and morphogen-gradient principles were supported as established developmental biology mechanisms but did not provide direct quantitative evidence for adult unconscious processes, and were therefore treated exclusively as a conceptual organizational layer. Available evidence supports PINE regulation and epigenetic mechanisms as empirically grounded contributors to multisystem integration relevant to unconscious/implicit regulation. Morphogenetic principles are best interpreted as a developmental organizing template rather than as empirically supported mechanisms of unconscious processing, generating testable hypotheses for future prospective and mechanistic studies. https://www.crd.york.ac.uk/prospero/, identifier [CRD42024594352].
Multiple endocrine neoplasia type 2 is an autosomal dominant hereditary syndrome characterized by a predisposition to medullary thyroid carcinoma and pheochromocytoma. The discovery of the RET proto-oncogene as the molecular driver of this syndrome has revolutionized the management of this disease, enabling presymptomatic diagnosis of medullary thyroid carcinoma, which leads to prophylactic thyroidectomy, screening for pheochromocytomas, and the discovery of systemic therapies that control advanced disease. This article reviews genotype-phenotype correlations, clinical manifestations, and current therapeutic strategies, including the use of selective tyrosine kinase inhibitors. In addition, we propose an algorithm for the treatment of advanced medullary thyroid carcinoma and metastatic pheochromocytoma.
Perioperative neurocognitive dysfunction (PND), a common complication associated with anesthesia and surgery, has garnered considerable interest regarding its underlying mechanisms. However, the precise pathways through which PND develops remain incompletely understood. Accumulating evidence suggests that dysfunction of the microbiota-gut-brain axis (MGBA) plays a pivotal role in the pathogenesis of PND. Accordingly, this article reviews current advances in the understanding of MGBA-mediated mechanisms contributing to PND, with a focus on neurological, endocrine, and immune pathways. Specifically, we discuss the involvement of the sympathetic, vagal, and enteric nervous systems, neuroinflammation within the central nervous system, the stress response and glucocorticoid signaling, microbial metabolites, and specific inflammatory factors and signaling pathways in the development of PND. Furthermore, targeting the gut microbiota may represent a promising therapeutic strategy for PND. This review aims to provide insights beneficial to both clinical management and future research on PND.
Therapeutic peptides are short chains of amino acids used to treat metabolic and endocrine conditions such as obesity and type 2 diabetes. While several peptide drugs have undergone rigorous approval processes that evaluate both safety and efficacy, novel, unapproved compounds have emerged and are rapidly expanding into preventive medicine and performance enhancement. Our objective is to present the effects, clinical applications, safety profiles, and regulatory status of prominent peptides used to treat several conditions. We reviewed 106 articles, prioritizing systematic reviews, meta-analyses, and randomized controlled trials in the PubMed, ScienceDirect, and SciELO databases. Our results suggest that therapeutic peptides are a promising tool for treating type 2 diabetes and obesity, for skin rejuvenation, and as hormone analogs for specific diseases and conditions. Although these are strategic and innovative options that can improve health, performance, and longevity, further studies are needed before most new peptides can be used safely in humans.
Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. Develop evidence-based recommendations related to the diagnosis and treatment of CPP. A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.
Per- and polyfluoroalkyl substances (PFAS) are extensively utilized in industrial and consumer applications, such as firefighting foams, textiles, electronics, industrial coatings, food packaging, and household consumer products, due to their excellent chemical stability. However, legacy long-chain PFAS are prohibited because of their endocrine-disrupting properties, bioaccumulative nature, and potential carcinogenicity, followed by the emergence of new alternatives, such as short-chain congeners and novel PFAS alternatives. PFAS are known to disrupt endocrine function, and the thyroid gland, a critical endocrine organ, is particularly vulnerable to their effects. Mother‒child populations are more likely to be affected by PFAS due to their specific physiological characteristics, metabolic differences, and developmental stages. This paper reviews the exposure levels of legacy PFAS and their alternatives in maternal and infant blood and breast milk, and the relationship between PFAS exposure and thyroid hormone (TH) levels. It also examines the similarities and differences in the mechanisms by which different PFAS affect thyroid function. Research has revealed that both legacy and PFAS alternatives have been detected in maternal blood, infant blood, and breast milk. While legacy PFAS exhibit higher exposure levels with notable regional variations, the concentrations of PFAS alternatives, although lower, remain a concern. PFAS exposure affects TH in mothers and infants, with legacy PFAS having a more significant effect. The mechanisms underlying thyroid disruption caused by different PFAS are largely similar. However, PFAS alternatives are characterized by high protein affinity, ability to disrupt fatty acid metabolism, and high hydrophilicity, and may also increase the risk of thyroid cancer (TC). This study provides critical evidence for evaluating the safety of PFAS alternatives and provides a scientific foundation for developing preventive and regulatory measures.
Fatigue is among the most prevalent and disabling symptoms in inflammatory bowel disease (IBD), affecting a substantial proportion of patients during active disease and persisting in many despite clinical remission. It is multidimensional, spanning physical, cognitive, and emotional domains, and it is a major determinant of health-related quality of life, work disability, and healthcare use. Correlations with conventional markers of intestinal inflammation are typically modest, indicating important contributions from extraintestinal, neuroimmune, nutritional, endocrine, sleep-related, and psychological mechanisms. This article is a narrative review with a structured literature synthesis, rather than a formal scoping review. The core search covered MEDLINE/PubMed, Embase, and the Cochrane Library from January 2010 to October 31, 2024, with targeted citation updates added during revision for recently finalized publications. Compared with recent broad reviews, the present manuscript adds three specific elements: explicit differentiation of evidence derived from primary randomized trials, prespecified patient-reported outcome analyses, and post hoc fatigue analyses; an updated synthesis of fatigue data for newer advanced therapies, particularly IL-23 and JAK-pathway agents; and a pragmatic biopsychosocial assessment-and-management framework with specific discussion of Arabic-language patient-reported outcome implementation and Middle East/North Africa practice considerations. Available evidence supports a stepwise clinical approach: First assess inflammatory activity and disease control; then screen systematically for reversible contributors including iron deficiency, other micronutrient deficits, endocrine abnormalities, sleep disorders, pain, mood disturbance, sarcopenia, and deconditioning. Validated instruments such as the Inflammatory Bowel Disease-Fatigue (IBD-F) questionnaire and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale are useful for serial monitoring. A clinically meaningful FACIT-Fatigue improvement appears to be context-specific; across IBD studies, approximately 6-10 points have the strongest empirical support, while trial-specific thresholds should be reported as originally prespecified. Biologic and targeted synthetic therapies can improve fatigue, but fatigue has rarely been a primary endpoint in pivotal trials. Anti-tumor necrosis factor agents, vedolizumab, ustekinumab, JAK inhibitors, and IL-23 inhibitors have all shown beneficial effects on fatigue-related outcomes, although the evidentiary strength varies from primary trial data to exploratory post hoc analyses. Nonpharmacological strategies including intravenous iron when indicated, exercise and rehabilitation, optimization of sleep and pain, and cognitive-behavioral or mindfulness-based interventions remain essential. Fatigue should therefore be recognized as a core manifestation of IBD and incorporated into routine patient-reported outcome assessment and treat-to-target discussions.
This study aims to provide a comprehensive overview of existing systematic reviews and meta-analyses, systematically summarizing the current evidence on the topic and exploring the relationship between processed meat (PM) consumption and various health outcomes. A systematic search was conducted in PubMed, Embase, and Web of Science databases for systematic reviews and meta-analyses examining the relationship between PM consumption and health outcomes from the inception of each database until May 2025. This is a descriptive umbrella review that summarizes existing systematic reviews and meta-analyses without conducting further quantitative re-analysis of summary estimates using random- or fixed-effects models or prediction intervals. A total of 34 articles and 54 meta-analyses were included in the review. Use the validated AMSTAR2 tool to assess the methodological quality of studies included in the meta-analysis, and use GRADE to assign the level of evidence quality. The key dose-response results reported below were selected based on their high public health relevance and stable effect estimates across the included meta-analyses. Consumption of PM was found to be associated with higher risks of various cancers, cardiovascular diseases, metabolic disorders, and all-cause mortality. Dose-response analysis revealed that an increase in PM consumption of 50 g/day was associated with a 72% higher risk of gastric cancer, 17% higher risk of colorectal cancer, 4% higher risk of prostate cancer, and an 8% higher risk of chronic obstructive pulmonary disease (COPD). All the above dose-response associations are based on low to very low certainty evidence as assessed by the GRADE system. Most studies suggest that PM consumption is associated with diseases such as cancer, cardiovascular diseases, and metabolic disorders, but the certainty of evidence for most outcomes is rated as low or very low by the GRADE system. Based on the report from the International Agency for Research on Cancer (WHO-IARC) and the World Cancer Research Fund (WCRF), no level of PM intake can be confidently considered safe for the prevention of chronic diseases such as colorectal cancer. Future research should include more well-designed prospective studies and randomized controlled trials to further explore the associations between PM consumption and various health outcomes.
Linear growth stunting increases a child's risk for mortality and lifelong morbidities. Understanding and preventing the causes of childhood stunting is a global health priority. The leading contributors to stunting are undernutrition and infection. Schistosomiasis, a neglected tropical disease, has long been associated with childhood stunting, but there are limited reviews summarizing the evidence. This narrative review examines cross-sectional associations between infection and linear growth, longitudinal impacts of schistosomiasis treatment on growth and the influence of schistosomiasis on the endocrine system, specifically the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis. After reviewing more than 60 years of research, there is evidence for an association between schistosomiasis infection and linear growth measures but mixed results relating to stunting, a categorical outcome based on low height-for-age measures. This may be due to limitations in study design or the length of time required to induce stunting. The reports also support the theory that schistosomiasis disrupts the GH/IGF-1 axis, resulting in reduced IGF-1 and impaired linear growth. These findings reinforce the need for early treatment interventions for children living in schistosomiasis-endemic regions and encourage research to include stunting risk factors and endocrine measures in future schistosomiasis study designs. This article is part of the theme issue 'Biological, biomedical and environmental drivers of stunting'.
Di(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer that has raised significant concerns due to its strong endocrine-disrupting effects, which are closely associated with developmental toxicity. While previous reviews have explored DEHP's developmental toxicity, this study uniquely focuses on recent (past 10 years) advances in understanding the molecular mechanisms behind DEHP-induced organ developmental disorders. It emphasizes key pathways involved in cellular proliferation, differentiation, and endocrine balance. Despite widespread human exposure to DEHP, translating preclinical findings to human health outcomes remains challenging due to variations in exposure levels, individual susceptibility, and limited clinical data. This review compiles the latest clinical research on DEHP-related developmental health risks, explicitly addressing these uncertainties and exposure-related factors. By combining new molecular insights with clinical relevance, this review offers a focused scientific basis for future research into DEHP's developmental toxicology, bridging the gap between preclinical mechanisms and real-world human exposure outcomes.
This umbrella review evaluates adverse childhood experiences (ACEs) as etiological risk factors for non-mental medical diseases. We systematically searched PubMed, EMBASE and WoS up to 30 April 2025, following PRISMA, PRIOR and MOOSE guidelines. Eligible studies were meta-analyses or systematic reviews investigating associations between ACEs and non-mental medical disease, with control groups and adequate data for extraction. Studies on congenital disorders or without relevant data were excluded. Methodological quality was assessed using AMSTAR. The protocol was registered in PROSPERO (CRD42022384104). Meta-analytic data were synthesised with random-effects models to calculate odds ratios (OR) with confidence intervals and p-values. Heterogeneity was assessed with I2, small-study effects with the Egger test, and 95% prediction intervals were calculated. Evidence credibility was graded according to Ioannidis' criteria. We included 36 reviews/meta-analyses covering 250 non-duplicated studies with 6,064,006 participants (412,760 cases and 5,651,246 controls). There was highly suggestive evidence (Class II) linking any ACE to any non-mental medical disease (OR = 1.57; 95% CI: 1.49, 1.66). Strong associations were found between any non-mental medical disease and abuse of any type (OR = 1.61), physical abuse (OR = 1.59), sexual abuse (OR = 1.58) and bullying (OR = 2.04). Regarding specific diseases, highly suggestive associations were identified for headache (OR = 1.91), irritable bowel syndrome (OR = 1.79), diabetes (OR = 1.67), and cardiovascular disease (OR = 1.46). Convincing evidence emerged for a modest association between ACEs and cardiovascular disease (OR = 1.19) and endocrine/metabolic disorders (OR = 1.62) in prospective studies. ACEs are significant risk factors for adult non-mental medical diseases, underscoring the importance of early intervention and prevention for vulnerable groups. Early stressors have lasting physical health impacts. Limitations include reliance on self-reported trauma and heterogeneous study designs; prospective data showed lower bias, reinforcing the need for rigorous research. Future studies should explore genetic, environmental, and resilience factors that may moderate medical risks among individuals exposed to ACEs. No funding was received.
Polycystic ovary syndrome (PCOS) is a complex multisystem disorder affecting 6%-13% of reproductive-aged women, characterized by hormonal and metabolic dysregulation. Driven by hyperandrogenism and insulin resistance, it contributes to reproductive and cardiometabolic complications. Current management remains largely symptom-focused, often limiting long-term effectiveness and comprehensive disease control. This narrative review critically evaluates current evidence on lifestyle-based and adjunct therapeutic strategies in PCOS management, with emphasis on dietary interventions, physical activity, nutraceuticals, and traditional remedies, focusing on their potential to modulate metabolic, endocrine, and inflammatory pathways alongside conventional clinical treatments. A structured narrative literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify studies published in English-language. Keywords related to PCOS, insulin resistance, hyperandrogenism, oxidative stress, lifestyle-interventions, dietary strategies, physical activity, traditional medicine, phytotherapy and mind-body interventions were combined using Boolean operators. Relevant original studies, clinical trials, systematic reviews, and meta-analyses were selected based on scope and relevance. Emerging evidence highlights the multifaceted role of lifestyle and adjunct interventions in improving the clinical outcomes in PCOS. Dietary approaches, including Mediterranean, low-glycemic index, ketogenic, and anti-inflammatory diets, are associated with improvements in metabolic parameters and insulin sensitivity. Structured physical activity comprising aerobic exercise, resistance training, high-intensity interval training, and mind-body practices such as yoga and Pilates demonstrates beneficial effects on metabolic and hormonal outcomes. Adjunct strategies, including nutraceuticals and selected phytochemicals, show potential in modulating insulin signalling, inflammation, and endocrine function. Psychological interventions, particularly mindfulness-based therapy and cognitive behavioural therapy, may alleviate psychosocial burden and enhance treatment adherence. Complementary cultural systems, including Ayurveda, Unani, and Traditional Chinese Medicine, have been explored as supportive approaches. Overall, heterogeneity in study design and quality necessitates cautious interpretation and further high-quality clinical validation. Effective PCOS management requires a balanced, evidence-based, and individualized approach in which lifestyle strategies form the foundation, pharmacological therapies remain central, and adjunct interventions are judiciously integrated as supportive measures rather than replacements for established care. Further well-designed high-quality clinical trials, standardized intervention protocols, and personalized therapeutic frameworks are needed to better establish the efficacy and safety of these strategies.
The survival of complex multicellular organisms depends on continuous inter-organ communication networks that coordinate organism-wide responses across physiological conditions and stress states, including adaptation to environmental challenges, infection, and injury. Rather than operating as isolated units, organ systems are integrated through interconnected signaling networks that transmit biological information across tissues. Building on prior work examining individual physiological pathways, this review introduces a unified systems-level framework that integrates inter-organ communication into a coherent model of organism-wide regulation. This review proposes a systems-level framework in which homeostasis is maintained through eight principal communication systems: neural, endocrine, immune-inflammatory, vascular, lymphatic, metabolic, microbiome-gut, and mechanical-structural. Epithelial barriers function as dynamic signaling interfaces within multiple systems, while extracellular vesicles act as cross-system mediators of information transfer rather than as independent communication networks. These systems operate across distinct temporal scales to coordinate host defense, metabolic adaptation, vascular regulation, and tissue repair. The framework further introduces a temporal hierarchy of signaling dynamics that links communication systems to phase-specific responses during physiological stress. Within this integrated network, glucocorticoid receptor α (GRα) is proposed to function as a systems-level regulator of inter-organ communication, supported by converging mechanistic, experimental, and clinical evidence, with variability in the strength of evidence across domains. In contrast to prior reviews, which addressed GRα function within individual systems, this work conceptualizes GRα as a central rheostat coordinating cross-system signaling and temporal transitions in homeostatic correction. Evidence was identified through hypothesis-driven searches using the Consensus AI platform and verified through manual review of primary biomedical literature. GRα, a ligand-activated transcription factor expressed in most nucleated cells, enables hormonal stress signals to coordinate gene-expression programs across tissues, modulating neuroendocrine responses, endothelial function, inflammatory signaling, metabolic regulation, microbiome-host interactions, and tissue remodeling. Systemic responses to stress progress through three phases of homeostatic correction-Priming, Modulatory, and Restorative-within which GRα supports integrated organism-wide adaptation. This integrative framework provides a mechanistic basis for understanding the emergence and temporal evolution of biological responses in health and critical illness.
Marine invertebrates are characterized by high species diversity, a wide distribution, ease of culture, low cost, short life cycles and high sensitivity to pollutants, which makes them excellent models for observing toxic effects and elucidating underlying mechanisms. This paper reviews representative species from three phyla-Arthropoda, Mollusca, and Echinodermata-under both single emerging contaminant exposure and combined exposure scenarios, and analyzes the reproductive and neurotoxic impacts of these contaminants on marine invertebrates. Neurotoxicity is mediated by several key mechanisms: inhibition of acetylcholinesterase activity; disruption of neurotransmitter balance, oxidative stress; and cellular damage, interference with embryonic neural development and axis specification, and impairment of neural cell differentiation and migration. Reproductive toxicity impairs reproductive development by disrupting endocrine signaling, inducing oxidative stress, downregulating reproduction-related genes and damaging gonadal structure. Studies have shown that, besides environmental factors, contaminant concentration is closely correlated with toxic potency and differing concentration ratios can lead to either antagonistic or synergistic effects in combined toxicity. Current research has largely focused on single or binary contaminant systems, whereas studies on multi-contaminant mixtures and their interactions with multiple environmental factors remain limited. Future research should prioritize combined exposure to multiple contaminants, long-term multigenerational observations and the development of comprehensive ecological risk assessment models and monitoring standards, thereby providing a scientific basis for marine ecological conservation.
Endometriosis affects approximately 10% of reproductive-aged women worldwide and is a leading cause of chronic pelvic pain. Despite its high prevalence and substantial socioeconomic burden, the mechanisms underlying endometriosis-associated pain remain incompletely understood, resulting in delayed diagnosis and limited therapeutic durability. Notably, pain severity frequently shows poor correlation with lesion burden, indicating that endometriosis-associated pain extends beyond the presence of endometriotic lesions alone. Accumulating evidence supports a model in which endometriosis-associated pain arises from the convergence of endocrine dysregulation, immune activation, aberrant neuroangiogenesis, and maladaptive neural plasticity, with estrogen dominance and progesterone resistance serving as central upstream drivers of pain biology. Estrogen-dependent inflammation and progesterone resistance establish a permissive microenvironment that promotes immune dysfunction, neurotrophic signaling, and nociceptor sensitization. These peripheral processes drive sustained afferent input to the central nervous system, leading to peripheral, central, and cross-organ sensitization that can perpetuate pain independently of lesion activity. In this review, we synthesize current evidence across the clinical spectrum of pain, mechanistic pathways, and therapeutic approaches in endometriosis. We integrate insights from inflammatory and immune pathways, neuroimmune crosstalk, hormonal regulation, and sensitization processes, emphasizing progesterone resistance and estrogen-mediated signaling as central modulators. Advances from preclinical models and emerging multi-omics technologies are highlighted to define pain signatures that transcend lesion-based classification. Finally, we discuss emerging therapeutic strategies targeting neuroimmune and endocrine pathways and propose a precision medicine framework that incorporates mechanistic biomarkers, translational models, and pain-specific clinical endpoints to improve stratification, reduce ineffective interventions, and achieve individualized pain relief for women with endometriosis.
Environmental exposures to endocrine-disrupting chemicals have emerged as significant risk factors underlying the etiopathogenesis of hypospadias, yet molecular mechanisms linking environmental factors to phenotypic outcomes remain poorly understood. This systematic review aimed to evaluate epigenetic alterations in human subjects with hypospadias and identify DNA methylation patterns contributing to the disease etiopathogenesis. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comprehensive literature searches were performed in PubMed/MEDLINE in June 2025 using terms including hypospadias, epigenetics, DNA methylation, and related concepts. Two reviewers independently conducted study selection, data extraction, and quality assessment using an adapted Joanna Briggs Institute's (JBI) Critical appraisal checklist. Eight studies (2011-2024) involving 182 patients and 146 controls from diverse geographical locations met the inclusion criteria. Various methodologies were employed including genome-wide methylation profiling, methylated-site display-amplified fragment length polymorphism, and quantitative RT-PCR. Key findings included: (1) hormone signaling dysregulation with androgen receptor downregulation and estrogen receptor alpha upregulation; (2) differential methylation patterns in genes regulating smooth muscle function, lipid transport, and developmental signaling; (3) inverse correlation between differentially methylated regions and phenotypic severity; (4) environmental factor associations with xenobiotic metabolism gene upregulation; and (5) tissue-specific epigenetic signatures with potential as noninvasive biomarkers. Epigenetic regulation represents a critical dimension in hypospadias etiopathogenesis. DNA methylation alterations are linked to disrupted hormonal signaling, developmental pathways, and environmental exposures. Novel candidate genes and tissue-specific signatures offer potential biomarkers and therapeutic targets. These findings provide translational insights for early diagnosis, prevention strategies, and targeted interventions, warranting validation through larger multicentric cohorts.