Neuroendocrine tumors (NETs) constitute a heterogeneous and predominantly malignant group of neuroendocrine neoplasms that arise from endocrine cells dispersed throughout the body. Their clinical presentation, biological behavior, prognosis, and therapeutic management vary considerably depending on the primary tumor location and hormonal activity. Despite substantial progress in understanding the biology of NETs, identifying reliable molecular biomarkers for diagnosis, prognosis, and prediction of treatment response remains a major challenge. Increasing attention has therefore been devoted to the molecular characterization of NETs, with particular focus on recurrent genetic alterations that may contribute to tumor initiation and progression. In this review, we summarize current knowledge and recent findings referring to certain genes involved in the tumorigenesis of pancreatic and intestinal neuroendocrine tumors. We chose the genes based on data from the COSMIC (Catalogue of Somatic Mutations in Cancer) database, which compiles somatic mutations identified across numerous human cancers. We outline the biological functions of these changes and discuss their potential prognostic and predictive role as molecular markers. We also discuss their clinical relevance in both sporadic and familial forms of NETs, alongside their implications for future research and personalized management strategies.
As the cross talk of the parasympathetic nervous system, the vagus nerve exerts organ-specific regulatory effects on hepatic and pancreatic endocrine homeostasis, yet its divergent innervation patterns and their implications for post-transplant functional recovery remain understudied. This review summarizes the anatomical and functional differences of the vagus nerve in the liver and pancreas, and discusses how surgical denervation and incomplete re-innervation affect endocrine recovery after liver and pancreatic transplantation. At the anatomical level, vagus nerve fibers in the liver are relatively sparse and travel along the portal tripa, mainly terminating in the perihilar blood vessels and biliary tract ecological loci, with limited direct parenchymal synapses. This structure is conducive to metabolic perception and indirect regulation of liver glucose flux, bile acid-dependent signaling, and inflammatory tension. In contrast, pancreatic vagus nerve input enters through periarterial/periductal channels and is relays through pancreatic ganglia, forming dense cholinergic efferent control over pancreatic islet α/β/δ cells, supporting rapid and precise insulin-glucagon coordination and counterregulation responses. Clinically, recent preclinical trials and translational studies demonstrate that vagal nerve integrity-often compromised during transplant surgery-serves as a pivotal prognostic marker for endocrine recovery: Preserved vagal innervation is associated with accelerated glucose metabolism normalization and reduced post-transplant complications (e.g., insulin resistance, graft rejection). Notably, frontier strategies such as intraoperative vagal nerve-sparing techniques, targeted neuromodulation (e.g., vagus nerve stimulation), and stem cell-derived neurotrophic factor delivery have shown promising potential in mitigating denervation-induced endocrine dysfunction. This review emphasizes that deciphering the organ-specific vagal innervation mechanisms holds great promise for optimizing precision transplant surgery and developing novel neuromodulatory therapies, which may revolutionize the prognosis of liver and pancreatic transplant recipients.
Background/Introduction: Prostate cancer (PCa) is the most commonly diagnosed malignancy among men and remains a major cause of cancer-related mortality worldwide. We aimed to evaluate whether radiomic features extracted from normal endocrine organs, combined with clinical variables, could predict clinical progression in patients with PSMA-negative prostate cancer. Materials and Methods: In this retrospective study, 101 men with biochemically recurrent prostate cancer and negative [18F]DCFPyL PET/CT scans were included. Radiomic features were extracted from the adrenal glands, thyroid, the hypothalamus-pituitary complex, and testes. Post-imaging variables were excluded to prevent temporal data leakage. Models were developed using a stratified train/test split framework with preprocessing and feature selection performed exclusively within the training subset prior to evaluation on the held-out test set. Performance was evaluated using AUC, accuracy, sensitivity, specificity, and Brier score, while bootstrap confidence intervals and DeLong analysis were used for statistical assessment. Results: Multimodal fusion models integrating CT radiomics, PET radiomics, and clinical variables demonstrated the strongest predictive performance. The highest-performing model combined TESTIS_CT and TESTIS_PET radiomics with clinical variables, achieving an AUC of 0.758 (95% CI: 0.653-0.849). Clinical-only models remained highly competitive, with the best configuration achieving an AUC of 0.727 (95% CI: 0.618-0.833). PET + clinical and CT + clinical models achieved AUC values of up to 0.733 and 0.729, respectively, while imaging-only models demonstrated substantially lower discrimination. Although endocrine organ radiomics numerically improved predictive performance and specificity, DeLong analysis demonstrated no statistically significant improvement beyond clinical variables alone. Discussion: These findings suggest that endocrine organ radiomics may provide complementary system-level imaging biomarkers reflecting tumor-host interactions in PSMA-negative prostate cancer. However, their incremental clinical value remains modest. Conclusions: Endocrine organ radiomics combined with clinical variables demonstrated promising predictive performance in PSMA-negative prostate cancer, particularly in multimodal fusion models. Nevertheless, the added value beyond clinical variables alone was not statistically significant and requires validation in larger independent cohorts.
Paraneoplastic endocrine syndromes (PESs) are hormonal disturbances associated with malignancies that result from tumor-related production of hormone-like substances, immune-mediated mechanisms, or dysregulated signaling pathways. While they are well recognized in lung and neuroendocrine cancers, their relevance in gastrointestinal tumors remains less clearly defined. This narrative review synthesizes current knowledge on paraneoplastic endocrine manifestations in gastrointestinal malignancies, based on a structured search of the literature in major databases, including PubMed, Scopus, and Web of Science. The analysis focuses on clinically relevant syndromes such as hypercalcemia, Cushing-like manifestations, disorders of water balance, hypoglycemia, and acromegaly, with emphasis on underlying mechanisms, associated tumor types, diagnostic approaches, and therapeutic considerations. Available evidence indicates that gastrointestinal tumors can produce a range of biologically active substances, leading to diverse endocrine manifestations that may precede tumor detection and influence disease course. Among these, hypercalcemia and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) are among the most frequently reported, while other syndromes, such as ectopic Cushing syndrome or tumor-related hypoglycemia, are less common but often associated with more severe clinical outcomes. Recognition of these manifestations has direct clinical implications, as they may support earlier diagnosis, contribute to prognostic assessment, and guide therapeutic management. Improved awareness and a multidisciplinary approach remain essential for optimizing outcomes in patients with gastrointestinal malignancies.
Endometriosis is a chronic, estrogen-dependent inflammatory disorder characterized by the ectopic implantation and persistence of endometrial-like tissue outside the uterine cavity. Despite its high prevalence and significant impact on quality of life, the pathogenesis of endometriosis remains incompletely understood and involves a complex interplay between hormonal dysregulation, immune dysfunction, and chronic inflammation. In recent years, growing evidence has highlighted the role of the microbiota as a potential modulator of these interconnected pathways. This review proposes an integrative framework in which the microbiota acts as a central modulator of immune-endocrine interactions in endometriosis, while synthesizing current evidence on underlying biological mechanisms. We discuss how alterations in the gut, vaginal, and endometrial microbiota contribute to disease pathophysiology through multiple mechanisms, including disruption of intestinal barrier integrity, activation of pro-inflammatory signaling pathways, immune dysregulation, and modulation of estrogen metabolism via the estrobolome. Microbial β-glucuronidase activity and enterohepatic recirculation of estrogens are explored as key processes linking gut dysbiosis to the hyperestrogenic environment characteristic of endometriosis. Furthermore, we review current pharmacological treatments and highlight their limitations, emphasizing the need for novel therapeutic strategies targeting upstream disease mechanisms. Emerging approaches, including probiotics, postbiotics, short-chain fatty acids, and dietary interventions, are discussed as promising adjunctive therapies capable of modulating inflammation, immune responses, and metabolic pathways. Although current evidence remains heterogeneous and largely derived from preclinical and observational studies, the microbiota emerges not only as a potential therapeutic target but as a key integrative node linking endocrine, immune, and metabolic pathways in endometriosis. Future research should focus on well-designed clinical trials to validate microbiome-based interventions and to define their role in personalized management strategies for endometriosis.
Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS-STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts.
Menstrual disorders are among the most common health problems faced by young women, yet effective interventions remain limited. Recent evidence has linked endocrine disruptors (EDs) to dysmenorrhea and premenstrual syndrome (PMS), suggesting that reducing exposure may alleviate symptoms. The aim of the study was to investigate the effects of an immersive virtual reality (VR) intervention designed to promote protective behaviors against EDs and to evaluate its longitudinal impact on menstrual pain and PMS among young adult women. A nonequivalent comparison group pretest and repeated posttest experimental design was applied, using a convenience sample of 30 participants. Guided by the Information-Motivation-Behavioral skills model, the immersive VR intervention incorporated educational content, motivational cues, and avatar-based play experiences to enhance knowledge, perceived benefits, and self-efficacy. The comparison group received a small-group education session. Data were collected at baseline and at 4, 8, 12, and 24 weeks post-baseline. Repeated-measures revealed significant interaction effects between group and time for menstrual pain (F = 2.67, p = 0.039), perceived benefits of protection from ED exposure (F = 4.41, p = 0.003), self-efficacy in reducing ED exposure (F = 5.42, p = 0.001), and protective behaviors against EDs (F = 4.68, p = 0.002). However, the overall group-by-time interaction effect for PMS was not statistically significant (F = 2.05, p = 0.097). Conclusion/Implication for Practice: Immersive VR as part of digital interventions has the potential to transform patient education by enhancing engagement while promoting protective health behaviors and improving associated health outcomes. Future research should explore strategies to improve long-term behavioral adherence and examine whether booster sessions can help sustain the effects of the intervention over time.
Estuarine ecosystems are increasingly threatened by organic ultraviolet absorbers (OUVs). However, their acute and combined toxicity to estuarine aquatic organisms at environmentally relevant concentrations remains poorly understood. This study evaluated the acute lethality and sublethal developmental toxicity of ethylhexyl salicylate (EHS), homosalate (HMS), and UV-329 on Mugilogobius chulae embryos. It also investigated the developmental effects and thyroid-related transcriptional responses of binary and ternary mixtures at environmentally relevant concentrations, and assessed their combined effects at both phenotypic and transcriptional levels. While individual exposure exhibited low acute lethality, co-exposure to binary and ternary mixtures increased embryonic mortality, although these changes were not statistically significant. Co-exposure significantly decreased embryonic heart rate (p < 0.05). Notably, at the tested environmentally relevant concentration, the heart rate response to the HMS + UV-329 mixture showed an interaction pattern consistent with potential synergism based on the CI and IA models, whereas other mixtures were classified as antagonistic. In addition, co-exposure significantly upregulated HPT axis-related genes (p < 0.05), suggesting potential perturbation of thyroid-related molecular pathways. Co-exposure to EHS + HMS and EHS + UV-329 showed synergistic effects on tg, but additive effects on tpo and nis, whereas HMS + UV-329 and the ternary mixture produced synergistic effects on all three genes. The ternary mixture significantly upregulated dio3, trhrα, tshr, and thrα (p < 0.05), and these responses were classified as synergistic at the tested environmentally relevant concentration. Overall, co-exposure to environmentally relevant concentrations of OUVs was associated with greater developmental and molecular-level responses in benthic fish embryos than did exposure to individual OUVs. These findings provide useful information for assessing the mixture toxicity of OUVs in estuarine environments, particularly with respect to early developmental effects in fish.
Environmental pollutants adversely affect both adult organisms and their offspring. Prednisone, a synthetic glucocorticoid frequently detected in surface water, harms aquatic organisms like sheepshead minnows, tadpoles, and zebrafish (Danio rerio). However, data on its effects on the thyroid endocrine system of zebrafish and its intergenerational toxicity are currently lacking. This study exposed adult male zebrafish to environmentally relevant prednisone concentrations (0-500 ng/L) for 60 days to explore potential thyroid endocrine disruption in both parents and offspring. Research findings show that compared with the control group, zebrafish in the high-dose (H) group had significantly reduced body length and weight. Their swimming speed decreased by 20.9-32.7%, the time spent stationary at the bottom of the tank decreased by 139.1-152.1%, and the frequency of this behavior dropped by 84.6-94.2%. As prednisone concentrations increased, the plasma levels of T4 in parental zebrafish decreased significantly, while the levels of T3 and TSH increased significantly. Thyroid follicular epithelial cells exhibited hyperplasia and hypertrophy along with a depletion of colloid cells. These effects were associated with abnormal transcriptional levels of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis (i.e., crh, pax8, tpo, tg, ttr and dio1 and dio2). Additionally, parental exposure to prednisone impaired F1 larvae: 82.3% increased mortality, 14.3-32.2% reduced hatching rates, abnormal heart rates, 29.16-38.76% reduced swimming activity, decreased thyroid hormones, and dysregulated transcription of HPT axis-related genes. The study confirms that prednisone induces intergenerational toxicity in parents and offspring by disrupting thyroid endocrine function, enhancing understanding of the risks posed by prednisone to fish.
Phthalate alternatives have emerged worldwide recently in response to concerns that traditional ortho-substituted phthalates alter and inhibit endocrine and reproductive functions and behave as endocrine disrupting chemicals (EDC). As a result, legacy plasticizers are being phased out of use, giving rise to alternative plasticizers. Human biomonitoring studies indicate that people are increasingly exposed to alternative plasticizers. However, recent studies suggest that alternative plasticizers may disrupt endocrine and reproductive functions. Foremost among these emerging substitutes are di-2-ethylhexyl terephthalate (DEHTP), a ring substitution isomer of the most common plasticizer phthalate di-2-ethylhexyl phthalate (DEHP), and tri-2-ethylhexyl trimellitate (TOTM), which has three ester side chains compared to DEHP and DEHTP's two. In this literature review, we provide a comprehensive overview of environmental monitoring and biomonitoring of DEHTP and other substituted benzene carboxylic acid derivatives used as phthalate alternatives, which together illustrate the widespread use of these compounds leading to human and environmental exposures as ubiquitous as phthalates. We also review reproductive toxicity findings in animals, in vitro, and human epidemiology. Overall, the availability of studies regarding the health impacts of alternative plasticizers is limited. Published literature suggests that these chemicals can disrupt hormone levels in rodents and zebrafish. This review underscores the urgent need for further research to characterize the long-term health impacts of these emerging chemicals and to prevent the regrettable substitution of one hazard for another.
Inflammatory bowel disease (IBD), including Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), frequently cooccurs with anxiety and depression, a comorbid pattern that severely impairs patients' quality of life and has thus attracted increasing attention in clinical practice. The gut-brain axis (GBA)-an intricate bidirectional communication network encompassing neural, immune, endocrine, and microbial pathways-serves as a key framework for unraveling the biological underpinnings of this comorbidity. This review systematically synthesizes existing literature to dissect the GBA mechanisms driving IBD-anxiety/depression comorbidity, focusing on four core inflammatory pathways: immune inflammation, gut microbiota-metabolite interactions, neural signaling, and the hypothalamic-pituitary-adrenal (HPA) axis. We also critically examine ongoing research controversies in inflammopharmacology and propose future breakthrough directions grounded in current evidence. Our synthesis reveals that these four pathways form a self-reinforcing inflammatory vicious cycle: intestinal inflammation may disrupt central nervous system (CNS) function through proinflammatory factors, microbiota-derived metabolites, and neural signals, thereby contributing to emotional disorders. Conversely, psychological stress and negative emotions may exacerbate intestinal inflammation via neural and endocrine pathways. Key controversies include unresolved causal relationships between IBD and emotional disorders, debates over dominant regulatory mechanisms, poor reproducibility of gut microbiota studies, and variable efficacy of single-target anti-inflammatory interventions. Moving forward, future research should leverage longitudinal cohort designs, advanced omics technologies, and artificial intelligence tools to deepen mechanistic insights. Developing multi-target anti-inflammatory interventions and robust biomarker systems will facilitate integrated gastroenterological and psychiatric care, enabling precise diagnosis and treatment to enhance patients' physical and mental rehabilitation.
Secondary hyperparathyroidism (SHPT) is a major component of chronic kidney disease-mineral and bone disorder (CKD-MBD), reflecting progressive disturbances in mineral metabolism, endocrine signaling, skeletal remodeling, and parathyroid-gland biology. Traditionally, preoperative parathyroid hormone (PTH) has been used primarily as a biochemical threshold for surgical referral. However, persistent PTH elevation in advanced CKD-related SHPT may reflect more than isolated endocrine activity; available evidence suggests it integrates parathyroid-gland remodeling, receptor resistance, skeletal turnover, treatment refractoriness, and systemic CKD-MBD severity. This review summarizes key molecular and cellular mechanisms of progressive SHPT, including diffuse-to-nodular hyperplastic transition, downregulation of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) signaling, disruption of the fibroblast growth factor 23 (FGF23)-Klotho axis, and activation of transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) proliferative pathways. Building on this mechanistic framework, we discuss how persistent PTH elevation has been linked to glandular remodeling, resistance to calcimimetic and vitamin D therapy, high-turnover renal osteodystrophy, hungry bone syndrome, altered intraoperative PTH kinetics, postoperative endocrine-skeletal remodeling, and long-term recurrence. Severe SHPT is also increasingly recognized as a systemic CKD-MBD phenotype associated with vascular calcification, cardiovascular risk, metabolic instability, and impaired quality of life. Within this framework, preoperative PTH is best interpreted as an integrated biomarker within a broader assessment of glandular remodeling, skeletal metabolic activity, endocrine resistance, and systemic CKD-MBD biology, rather than as an isolated biochemical threshold.
Activating transcription factor 3 (ATF3) functions as a central regulator of metabolic homeostasis across multiple physiological systems. A bibliometric analysis of ATF3 research (1993-2025) demonstrates an exponential growth trend, particularly in metabolic disease research demonstrating a robust 14.15% annual growth rate, underscoring ATF3's emerging importance in metabolic regulation. This review synthesizes current knowledge of ATF3's multisystem regulatory functions, spanning endocrine, cardiovascular, nervous, immune, respiratory, digestive, and urogenital systems, and explores the molecular mechanisms by which ATF3 coordinates cellular stress responses, metabolic adaptation, and tissue-specific homeostasis. Particular emphasis is placed on ATF3's regulation of perivascular adipose tissue (PVAT) and its contribution to obesity-related vascular dysfunction. Atf3 deficiency profoundly alters PVAT structure, adipocyte browning capacity, inflammatory signaling, and insulin sensitivity, establishing ATF3 as a critical determinant of adipose-vascular crosstalk. We further evaluate emerging therapeutic strategies targeting ATF3, including natural compounds (Salvia miltiorrhiza derivatives, sulfuretin) and synthetic modulators (SW20.1, ST32 series), that show promise in experimental metabolic disorders. Current challenges in therapeutic translation include achieving tissue-specific targeting and optimizing drug delivery systems. This comprehensive analysis positions ATF3 as a master regulator linking stress responses with metabolic homeostasis, highlighting its potential as a therapeutic target for obesity-related metabolic and vascular disorders.
Background/Objectives: Breast cancer is the most common malignancy in young women, many of whom face fertility impairment due to gonadotoxic treatments and prolonged endocrine therapy. Ovarian tissue cryopreservation (OTC) has emerged as an alternative fertility preservation (FP) strategy, particularly when controlled ovarian stimulation is not feasible. This study aimed to evaluate the role of OTC in breast cancer patients, with the aim of clarifying its current clinical role and future perspectives within fertility preservation counselling for this population. Methods: A structured SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis was conducted based on the current literature, addressing clinical efficacy, safety, and applicability of OTC in breast cancer patients. Results: Key strengths of OTC include the absence of delay in cancer treatment and the potential to restore both endocrine and reproductive function. However, limitations include the need for surgery, the theoretical risk of reintroducing malignant cells, and variable, less predictable reproductive outcomes compared with gamete-based strategies. Opportunities lie in advances in cryopreservation, transplantation techniques, and integration with in vitro maturation. Major threats include limited data in breast cancer-specific populations, challenges in BRCA mutation carriers, and low utilization rates affecting cost-effectiveness and healthcare sustainability. Conclusions: OTC represents a valuable complementary FP option for selected breast cancer patients, particularly in urgent settings. Despite promising outcomes, its use should remain individualized within multidisciplinary counseling, considering patient-specific oncological and reproductive factors, while further research is needed to clarify long-term safety and efficacy.
Postpubertal cryptorchidism remains clinically challenging, as patients often present with long-standing maldescent, impaired spermatogenesis, and an increased risk of testicular malignancy. However, the optimal management of this population remains controversial, and comprehensive data on clinical characteristics, surgical outcomes, endocrine changes, and spermatogenic damage are still limited. We conducted a single-center retrospective cohort study of 194 patients (210 undescended testes) undergoing primary orchiopexy between January 2018 and June 2024. Clinical characteristics, testicular position, ultrasonographic volume, semen parameters, endocrine parameters, and histopathology findings were collected. Intraoperative biopsies were obtained in 200 testes (95.2%) and graded using the Johnsen score. Severe spermatogenic impairment was defined as a Johnsen score ≤3; analyses of spermatogenic impairment were performed in 164 patients with available histological and endocrine assessments. Surgical outcomes were assessed in 185 testes with ≥3-month follow-up, and oncologic events were assessed in 155 patients (161 testes) with available follow-up data. Univariable and multivariable logistic regression analyses were performed to identify predictors of severe spermatogenic impairment. Most undescended testes were in a high position (196/210, 93.3%), and the affected testis had reduced volume in unilateral cases (median 6 vs. 18 mL). Overall anatomical success at 3 months was 80.0% (148/185), with recurrence and atrophy rates of 9.7% and 10.3%, respectively. Among patients with available semen data, unilateral cases showed no azoospermia, but 16 of 44 patients (36.4%) had at least one abnormality in sperm concentration, progressive motility, or normal morphology; by contrast, bilateral cases frequently presented with azoospermia or extremely low sperm counts. In unilateral cases, testosterone, LH, and FSH remained within the normal range without significant perioperative change; in bilateral cases, testosterone was generally preserved whereas FSH was elevated and remained above normal at follow-up. Histologically, only 17 of 200 biopsied testes (8.5%) had a Johnsen score >8, and 71/164 (43.3%) showed severe spermatogenic impairment. High testicular position was strongly associated with severe impairment (univariable OR 6.50, 95% CI 2.15-19.64, p < 0.001) and remained an independent predictor in multivariable analysis (adjusted OR 6.01, 95% CI 1.95-18.49, p = 0.002); affected testicular volume was independently inversely associated with severe impairment (adjusted OR 0.78 per 1 mL, 95% CI 0.64-0.95, p = 0.013). During a median follow-up of 54.6 months (range 12-78), one patient (0.5%) developed ipsilateral seminoma 48 months after orchiopexy. In postpubertal cryptorchidism, histological and functional spermatogenic impairment is often established before surgery and is unlikely to be substantially reversed by orchiopexy. The main value of orchiopexy lies in anatomical repositioning, pathological assessment, and facilitation of long-term surveillance. High testicular position and smaller preoperative testicular volume identify a subgroup at particularly high risk of severe spermatogenic failure, and malignancy risk is not eliminated, supporting the need for long-term follow-up.
Intermittent fasting (IF) has emerged as a popular dietary intervention with potential metabolic and endocrine benefits. However, its effects on sexual function and reproductive health remain incompletely understood. This comprehensive review synthesizes current evidence from human clinical trials and animal studies examining the impact of various IF protocols-including time-restricted eating (TRE), alternate-day fasting (ADF), and Ramadan fasting-on male and female sexual function, reproductive hormones, and fertility outcomes. In males, limited human data suggest preserved erectile function but reduced sexual desire during Ramadan fasting, with neutral effects on testosterone in obese adults undergoing TRE. Animal studies demonstrate context-dependent effects, with IF protecting against high-fat diet-induced reproductive dysfunction while potentially impairing spermatogenesis under prolonged energy restriction. In females, IF shows promise for improving hyperandrogenism and menstrual regularity in polycystic ovary syndrome (PCOS), mediated by enhanced insulin sensitivity and reduced free androgen index. However, direct measurements of female sexual function domains (libido, arousal, lubrication, orgasm) are largely absent from the literature. Mechanistic pathways involve modulation of the hypothalamic-pituitary-gonadal (HPG) axis, insulin-adipokine signaling, sex hormone-binding globulin (SHBG), and oxidative stress pathways. Evidence quality is limited by small sample sizes, heterogeneous protocols, short follow-up periods, and predominance of animal data. While IF may offer reproductive benefits in metabolically compromised populations, particularly women with PCOS, caution is warranted in young, lean, or energy-deficient individuals. Future research should employ standardized IF protocols, validated sexual function instruments, and long-term fertility endpoints to establish evidence-based clinical recommendations.
Pain exhibits significant circadian rhythmic characteristics, sharing a bidirectional regulatory relationship with the biological clock. Circadian rhythm disruption has been confirmed as an important risk factor for various chronic pain conditions, severely affecting patients' pain perception and treatment response. This narrative review was informed by searches of PubMed, Web of Science, Scopus, and Google Scholar (January 2000-March 2026), supplemented by backward citation tracking.We synthesize recent advancements in molecular biology and neuroscience to elucidate the interplay between circadian rhythms and pain. Furthermore, it evaluates the clinical potential of rhythm-based intervention strategies. Emerging evidence indicates that circadian rhythms dictate pain pathogenesis by modulating core clock gene expression, endocrine signaling, and neuro-immune functions. While the diurnal patterns of pain perception are well-documented, recent studies have begun to unravel the underlying molecular mechanisms and neural circuitry. Notably, circadian misalignment exacerbates pain sensitivity and diminishes the potency of conventional analgesic treatments. Circadian biology is pivotal to modern pain management. Leveraging rhythm-based strategies offers a novel paradigm for the individualized treatment of chronic pain. This review provides a theoretical framework and practical insights for future mechanistic research and precision clinical practice. For many people, pain changes during the day. It might feel worse in the morning, afternoon, or night. This happens because of how we sleep, how much we move, when we take medicine, and our body’s natural clock. We read many studies to learn how this inner clock controls pain and why taking medicine at the right time matters. We found that pain goes up and down because of our body clock, but also because of our habits, light, and bad sleep. The idea of treating pain at exact times is a good one, but doctors still need more proof. We do know that taking everyday pain pills or sleep medicine at certain times can really help. However, many other ideas have only been tested on animals so far, not people. In the future, scientists need to do better tests on humans. Using smart watches and simple health tests could help doctors find out who will feel better by taking their medicine at the perfect time.
Reactivating functional estrogen receptor alpha (ERα) expression represents a promising strategy for tamoxifen (TAM)-based endocrine therapy in triple-negative breast cancer (TNBC). However, TAM and its metabolites may exert potential oncogenic effects, which could compromise TAM efficacy in TNBC. Here, we report that low-dose 4-hydroxytamoxifen (4-OHT), an active metabolite of TAM, enhances stemness in TNBC cells via the Neuropilin-1 (NRP-1)/Calpain-2 (CAPN2)/β-catenin axis. Mechanistically, 4-OHT stimulates CAPN2 activation by promoting its membrane localization, increasing substrate cleavage, and inducing degradation of its endogenous inhibitor calpastatin. Activated CAPN2 suppresses ubiquitin-mediated degradation of β-catenin, leading to elevated β-catenin stability and intracellular accumulation. This enhances β-catenin transcriptional activity and ultimately promotes stemness in TNBC cells. Kaplan-Meier survival analysis showed that high NRP1 expression correlates with poorer overall survival in breast cancer patients undergoing endocrine therapy. Moreover, 4-OHT triggers Ca2+ release and ERK phosphorylation in TNBC cells through the NRP-1/PLC-γ1 pathway, thereby activating CAPN2. Finally, we demonstrate that the NRP-1 inhibitor EG00229 sensitizes ERα-re-expressing TNBC cells to TAM treatment. Our study uncovers a molecular mechanism by which 4-OHT promotes TNBC stemness via the NRP-1/CAPN2/β-catenin signaling cascade. Targeting NRP-1 may serve as a valuable strategy to improve TAM efficacy in ERα-re-expressing TNBC.
DiGeorge Syndrome (DGS), or 22q11.2 deletion syndrome, is a multisystem genetic disorder characterized by distinct craniofacial features and profound endocrine alterations, particularly parathyroid dysfunction and chronic hypocalcemia. This study aimed to non-invasively evaluate the microarchitecture of mandibular trabecular bone in pediatric patients with DGS using fractal dimension (FD) analysis on panoramic radiographs, aiming to better understand the localized radiographic impact of systemic calcium dysregulation and its implications for clinical management. Eleven pediatric patients diagnosed with DGS and eleven healthy, age- and sex-matched controls were enrolled. FD values were calculated using the box-counting method via ImageJ software across specific mandibular regions, including the condylar, gonial, and interdental areas. To assess measurement reliability and potential bias, a within-subject comparison of the right and left region of interests (ROIs) was conducted using the Wilcoxon signed-rank test. Regional influences of age and gender were evaluated using Spearman's correlation and Mann-Whitney U tests. A statistically significant reduction in trabecular complexity was identified in the right condylar region of the DGS group (p = 0.005). No significant differences were observed between the right and left corresponding ROIs (p > 0.05), indicating an absence of measurement bias. While gender did not influence FD values, a localized moderate negative correlation was found between age and FD specifically in the left gonial region (r =-0.427, p = 0.047). The reduction in localized mandibular trabecular complexity in children with DGS serves as a localized radiographic biomarker of the syndrome's underlying endocrine and calcium signaling disruptions. Safely managing the complex dentofacial needs of this vulnerable population requires a paradigm shift from isolated dental care to a closely coordinated, interdisciplinary approach involving pediatric endocrinologists, pediatricians, and pediatric dentists.
Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by hyperandrogenism, chronic anovulation, and insulin resistance, with hyperinsulinemia playing a pivotal role in exacerbating ovarian dysfunction. Although berberine (BBR) exhibits insulin-sensitizing properties, its therapeutic potential is limited by poor oral bioavailability. Our previous study developed BBR cocrystals with gallic and gentisic acid, achieving a 1.8-fold increase in Cmax to overcome bioavailability issues. The present study evaluated berberine-gallic acid (BBR-GAL) and berberine-gentisic acid (BBR-GEN) using an integrated in silico and in vivo approach in a letrozole-induced PCOS mouse model. Molecular docking simulations suggested stronger predicted binding of BBR relative to gallic acid and gentisic acid across all receptor systems, supporting its role as the dominant binder. Further, the coformers exhibited weaker but spatially proximal interactions, indicating potential indirect effects on the local binding environment. In vivo, letrozole administration induced hallmark PCOS features, including weight gain, impaired glucose tolerance, hyperandrogenism, ovarian inflammation, and disruption of hepatic insulin signaling. Treatment with BBR-GAL and BBR-GEN significantly improved metabolic parameters and restored insulin responsiveness. Notably, treatment with cocrystals was associated with increased adenosine monophosphate-activated protein kinase activation and reduced insulin receptor substrate-1 Ser307 phosphorylation, leading to enhanced phosphatidylinositol 3-kinase/protein kinase B signaling. Furthermore, treatment attenuated ovarian inflammation by downregulating interleukin 1-beta, interleukin 6, and tumor necrosis factor-alpha, and normalized luteinizing hormone receptor and androgen receptor expression. Collectively, these findings support the further investigation of BBR-GAL and BBR-GEN as multitarget agents that integrate insulin sensitization, antiinflammatory activity, and hormonal regulation for the management of PCOS. SIGNIFICANCE STATEMENT: This study demonstrates that crystal-engineered BBR cocrystals show improved efficacy against metabolic and reproductive dysfunction in an experimental model of PCOS. By restoring hepatic insulin signaling through modulation of the adenosine monophosphate-activated protein kinase-insulin receptor substrate-1/phosphatidylinositol 3-kinase/protein kinase B axis and attenuating ovarian inflammation, these formulations provide mechanistic validation for improved therapeutic efficacy. These findings indicate that crystal-engineered BBR could be a useful approach in improving the endocrine-metabolic phenotypes of preclinical PCOS.