Search Results (1,973)

Breast cancer (BC) is the most incidental cancer in women. Patients’ living conditions and survival rates have significantly improved with the success of two first-line endocrine therapies of selective estrogen-receptor modulators (SERMs from 1977) and aromatase inhibitors (AIs from 1995). Unfortunately, both therapies have produced significant resistance. AI resistance reaches 50% in metastatic estrogen-dependent BC cases, leading oncologists to seek a substitute for current therapies. We target the reductive 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), which stimulates the synthesis of the active estrogen estradiol (E2) and reduces the potent androgen dihydrotestosterone (DHT) simultaneously, triggering negative feedback on 17β-HSD7 expression. INH7(464), an improved 17β-HSD7 inhibitor, efficiently blocks estrogen conversion at an IC₅₀ of 92 ± 8 nM. INH7(464) inhibited cell proliferation by decreasing E2 levels and restoring DHT, successively arresting the cell cycle in G0/G1 phase. In vivo, INH7(464) reduced tumor size by 49% on Day 22 in BC xenografts with T47D. INH7(464) reduced E2 levels in mouse blood circulation and xenograft tumor tissue. There is no demonstrated cytotoxicity or cardiotoxicity of INH7(464) on cellular levels and mouse models under the experimental conditions. 17β-HSD7 is a potential target for estrogen-dependent BC therapy, while INH7(464) is promising for a preclinical lead compound (PCT/CA2022/050966). Full article

Walnut (Juglans regia L.) is a monoecious species with far more male than female flowers, yet the molecular mechanisms regulating sex differentiation remain largely unexplored. In this study, we investigated the effects of exogenous brassinolide (BR) on the female-to-male flower bud ratio and its regulatory mechanisms. We identified 23 April to 13 May as the critical physiological differentiation period for the ‘Xin xin 2’ variety. Exogenous application of 0.05 mg/L BR during this period significantly increased the female-to-male flower bud ratio across three consecutive years (2023–2025). Hormone metabolomics revealed that BR treatment induced sex-specific changes in ethylene and auxin contents. Transcriptomic analysis showed that BR differentially regulated MADS-MIKC genes in female and male buds. Integrated miRNA-mRNA analysis identified sex-specific regulatory modules targeting MADS-MIKC genes, including four in female buds and two in male buds. RT-qPCR and dual-luciferase assays confirmed that jre-miR156g directly targets the 3’-untranslated region of JrSPL5, with reciprocal expression patterns. Collectively, our findings demonstrate that exogenous BR increases the female-to-male flower bud ratio in walnut through multi-layered regulation involving hormone signaling, sex-specific expression of MADS-MIKC genes, and miRNA-mRNA regulatory cascades. This study provides a theoretical basis for breeding high-yielding walnut varieties by manipulating sex expression. Full article

The reproductive and developmental toxicity of diquat (DQ), a widely used herbicide, during pregnancy remains insufficiently characterized. This study investigated the effects of repeated DQ exposure on fetal development and maternal metabolism in pregnant Sprague–Dawley rats. The rats were administered sublethal doses of DQ (28.88 and 57.57 mg/kg), and maternal serum sex hormones, fetal skeletal development, and serum metabolomic profiles were evaluated. Compared with controls, serum estradiol levels were significantly decreased in the high-dose exposure group, whereas luteinizing hormone and follicle-stimulating hormone levels remained unchanged. Significant alterations in malondialdehyde, superoxide dismutase, and glutathione levels indicated oxidative stress in exposed rats. Severe fetal skeletal ossification deficits and developmental delays were observed, with incomplete or failed ossification of the occipital bone, sternum, caudal vertebrae, and pelvis, with litter-level incidences reaching 100%. Metabolomic analysis identified distinct serum metabolic profiles between DQ-exposed and control groups, suggesting ovarian steroidogenesis, phenylalanine metabolism, and aldosterone synthesis and secretion as key pathways affected by DQ toxicity. These findings suggest that repeated maternal exposure to DQ induces oxidative stress, disrupts metabolic and hormonal homeostasis, and causes delayed fetal skeletal development. This study provides novel evidence for understanding the reproductive and developmental toxicity of DQ and its potential metabolic mechanisms. Full article

Obesity is a multifactorial condition that profoundly affects female reproductive health through endocrine, metabolic, and inflammatory mechanisms that disrupt the hypothalamic–pituitary–gonadal (HPG) axis. Women with obesity frequently develop menstrual irregularities, anovulation, amenorrhea, infertility, polycystic ovary syndrome (PCOS), impaired endometrial receptivity, and adverse pregnancy outcomes. Central obesity and insulin resistance contribute to hyperinsulinemia, reduced sex hormone-binding globulin (SHBG) levels, hyperandrogenism, altered gonadotropin secretion, and impaired folliculogenesis, while adipokines such as leptin and chronic inflammation further impair ovarian steroidogenesis and ovulatory function. Obesity-related oxidative stress and lipotoxicity also negatively affect oocyte quality, embryo development, implantation, and assisted reproductive technology outcomes, increasing the risk of gestational diabetes, preeclampsia, miscarriage, and preterm birth. This review evaluates the therapeutic potential of pharmacological weight-loss therapies in obesity-associated female reproductive dysfunction. A comprehensive literature review was conducted using various databases, focusing on anti-obesity pharmacotherapy on obesity, infertility and fertility in reproductive-aged women. Evidence suggests that several FDA-approved and off-label anti-obesity agents, including orlistat, liraglutide, semaglutide, phentermine/topiramate, bupropion/naltrexone, metformin, exenatide, and tirzepatide, may improve reproductive outcomes primarily indirectly through weight reduction and metabolic improvement. GLP-1 receptor agonists, particularly liraglutide, semaglutide, and exenatide, appear especially promising, demonstrating beneficial effects on insulin sensitivity, menstrual regularity, ovulation, androgen levels, and pregnancy rates in women with PCOS. Tirzepatide, a dual GLP-1/GIP receptor agonist, has shown potent weight-loss and metabolic effects with potential indirect fertility benefits. Metformin improves insulin sensitivity and is widely used in PCOS to regulate androgen levels and restore ovulation, although its effects on pregnancy and live birth rates remain controversial. However, evidence for several agents remains limited, and concerns persist regarding reproductive safety during pregnancy. Overall, anti-obesity pharmacotherapy may represent an important adjunctive strategy for improving reproductive and metabolic health in women with obesity, although larger randomized clinical trials are still required. Full article

The aim of this study is to investigate how external nutrient supply affects the allocation of reproductive energy during artificial ripening of American eels (Anguilla rostrata), as well as the physiological regulatory mechanisms involved in their bodies. Healthy female American eels were selected for the experiment and randomly divided into two groups: feeding group and starvation group (simulating the natural migration of American eels without eating). The initial weight of the feeding group was (308.43 ± 36.99 g), and the initial weight of the starvation group was (291.67 ± 63.31 g). The entire experiment was divided into two stages: the first stage was a 6-month nutritional reinforcement period, during which the feeding group was regularly fed with Vannamei shrimp, while the starvation group was not fed throughout the entire process. The second stage was a 3-month artificial ripening stage, during which both groups of eels stopped feeding. Inject 1 mL of mixed hormone (containing 6.5 mg of carp pituitary extract CPE+200 IU human chorionic gonadotropin HCG per mL per week) into each eel for a total of 12 injections to induce gonadal maturation. Both groups of eels did not die during the experiment, with a survival rate of 100%. As the gonads continue to develop and mature, the growth and development advantages of the feeding group of eels are very obvious: body weight, chest circumference, and gonadal index are significantly higher than those of the starvation group. After completing 12 hormone injections, the gonadal index of the feeding group reached (32.72 ± 7.01%), while that of the starvation group was only (4.35 ± 2.48%). Under artificial ripening conditions, the egg diameter of the feeding-eel group increased rapidly in the later stage of the experiment. The growth rate of eggs in the starvation group was slow, and the final egg diameter was significantly smaller. The diameters of the nuclei of both groups of oocytes increased synchronously with the progress of the experiment; the number of nucleoli in the feeding group first increased and then decreased, while the number of nucleoli in the starvation group continued to increase. The oil droplets inside both sets of eggs gradually increased in size, and the oil droplets fed to the eggs in the middle and late stages of maturation had a larger volume. Hormone test results showed that the testosterone (T) level in the eel fed group increased significantly in the later stage of the experiment. This indicates that adequate nutrition can alleviate the inhibition of the reproductive endocrine axis through positive feedback regulation of the pituitary gonad (BPG) axis. Nutritional reinforcement before ripening can promote gonadal development and enhance reproductive capacity by regulating the distribution of nutrients between muscles and gonads. The results of this study provide a solid theoretical basis for improving the nutritional management plan for parent fish in the fully artificial breeding process of American eels. Full article

Background/Objectives: Korea has experienced rapid and heterogeneous shifts in cancer epidemiology since 1999. We aimed to characterize divergent incidence trajectories across the 24 major cancer types, quantify sex-specific burdens, and project case counts through 2030. Methods: Annual incidence data—including new case counts and age-standardized incidence rates (ASIRs) per 100,000 (2020 Korean standard population) stratified by sex—were extracted from the KCCR via the Korean Statistical Information Service (KOSIS) for 1999–2023. Annual percent change (APC) was estimated by log-linear regression with 95% confidence intervals (CIs). Holt–Winters damped exponential smoothing generated 2024–2030 projections with 95% prediction intervals (PIs). Changes in case ascertainment and coding over the study period were considered in interpretation. Results: Total incidence increased from 101,854 (1999) to 288,613 cases (2023), a 183.4% increase. Overall ASIR rose from 402.7 to 522.9 per 100,000. Of the 24 cancer types, 15 showed statistically significant increasing ASIR trends, 6 showed significant decreasing trends, and 3 showed no significant change. The highest-APC cancers were thyroid (+7.56%), prostate (+6.98%), testis (+5.39%), breast (+5.03%), and corpus uteri (+5.03%; all p < 0.001). The largest significant declines occurred in cervix uteri (−3.81%), larynx (−3.18%), liver (−2.90%), and stomach (−2.20%; all p < 0.001). Female ASIR increased from 294.7 to 488.9 per 100,000 (+65.9%); male ASIR increased from 573.3 to 587.0 per 100,000 (+2.4%). Total cancer incidence is projected to reach 307,091 (95% PI: 281,200–332,983) in 2026 and 330,213 (95% PI: 290,663–369,763) by 2030, with the steepest projected relative growth for prostate (+48.9%), kidney (+33.7%), and breast (+31.3%) cancers. Conclusions: Korean cancer epidemiology is undergoing a pronounced transition from infection-related toward metabolic, hormonal, and aging-related malignancies, with a marked and widening sex-specific divergence. Cancer-type-resolved projections through 2030 provide an evidence base for strategic capacity planning in Korean oncology. Full article

Purpose: Hypertension in women is a dynamic, hormone sensitive condition shaped by cumulative physiological changes across the life course. This review summarises current evidence relating vascular ageing, hormonal regulation, metabolic dysfunction, and reproductive history to blood pressure regulation in women. Materials and Methods: A narrative review of the literature was conducted using PubMed, Scopus and Google Scholar. Clinical, epidemiological, and mechanistic studies were synthesised to evaluate factors influencing hypertension in women. Reports in which menopausal status was not defined, or previous reproductive milestones were not documented, were excluded or interpreted with caution. Results: Evidence suggests that menopause, vascular ageing, metabolic dysfunction, androgen to oestrogen balance, and reproductive history interact to influence endothelial function, neurohormonal regulation, renal sodium handling, and vascular resistance. Ageing-related mechanisms, including cellular senescence, chronic low-grade inflammation, and genetic susceptibility, may contribute to increased cardiovascular risk. Hypertensive disorders of pregnancy identify women who are at higher risk of developing cardiovascular disease later in life and provide an opportunity for earlier risk assessment and prevention. Emerging therapies, including GLP-1 receptor agonists and SGLT2 inhibitors, may offer additional options for improving cardiovascular risk management, although their role in sex-specific prevention remains an evolving area of research. Conclusions: Hypertension in women is best understood within a life-course framework. Incorporating reproductive history, menopausal status, metabolic health, and emerging risk markers may improve cardiovascular risk assessment and support earlier intervention. Full article

Women with polycystic ovary syndrome (PCOS) have a substantially increased risk of endometrial cancer (EC), yet the biological mechanisms underpinning this association, to support future prevention and therapeutics, remain incompletely understood. Insulin-like growth factor (IGF)-associated signaling has been implicated, but existing evidence is conflicting. In this pilot translational study, serum IGF1 and IGFBP-3 were measured in women with PCOS (n = 12 for IGF1 and n = 6 for IGFBP-3) and controls (n = 24 for IGF1 and n = 7 for IGFBP-3). Pooled serum, stratified by IGF bioactivity, was applied to human EC cells to further assess effects on cell viability, cell cycle distribution, and downstream signaling. Computational analysis of publicly available endometrial cancer datasets was used to contextualize experimental findings. Serum IGF1 and IGFBP-3 levels did not differ significantly between PCOS and control groups. However, pooled PCOS serum was associated with increased EC cell viability, altered cell cycle progression and PI3K/AKT/mTOR signaling compared with control serum in this exploratory model. Pharmacological inhibition of IGF1R partially attenuated these effects, suggesting that IGF-associated pathways may contribute but are unlikely to act in isolation. In silico analysis identified frequent alterations in PI3K/AKT/mTOR-related genes in EC, consistent with pathway-level vulnerability rather than IGF1-specific dependence. These findings suggest that PCOS serum contains factors that are associated with increased EC cell viability and altered signaling pathways with partial involvement of IGF signaling; however, these findings should be interpreted cautiously given the exploratory pooled-serum design, small subgroup sizes, and use of a single EC cell line. However, multiple metabolic and hormonal pathways are likely to contribute. Larger, better-controlled studies incorporating insulin, sex steroids, and multiple EC models are required before causal inferences can be made. Full article

Background: Thyroid function tests are frequently requested, but manufacturer reference intervals often lack age- or sex-based stratification. This study established indirect reference intervals for thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) in a large adult population. We evaluated unsupervised algorithms and conventional partitioning to identify subgroups, compared multiple limit estimation methods, and assessed the diagnostic performance of the derived intervals against an independent, clinically defined external validation cohort. Methods: Data from 37,255 adults (age ≥ 18) collected between 2022 and 2024 were analyzed; a reference population of 5870 individuals was established following standardized exclusion criteria. Age-based subgroups were identified through hierarchical clustering with the Elbow method, and variable importance was assessed using Random Forest analysis. Reference intervals were calculated using non-parametric, Bhattacharya, refineR, and reflimR algorithms, applied to three population frameworks: (1) the total population without stratification, (2) subgroups derived from hierarchical clustering and (3) subgroups defined by the conventional Harris–Boyd partitioning method. Diagnostic performance was subsequently evaluated in an independent external cohort (National Health and Nutrition Examination Survey [NHANES]; N = 2297) for all estimated reference intervals. Three classification scenarios were assessed: TSH-only, fT4-only, and combined TSH + fT4, with sensitivity, specificity, Youden index, and decision curve analysis performed for each. Results: Random Forest analysis identified age as the dominant variable influencing TSH, fT4 and fT3 distributions (mean decrease in accuracy: TSH 41.62, fT4 44.18, fT3 43.7), while sex showed the lowest impact. Clustering yielded six age-based subgroups for analytes. Harris–Boyd partitioning yielded six age-based subgroups for TSH, two sex-based subgroups for fT4, and six combined age-and-sex subgroups for fT3. TSH limits were broadly concordant across all three approaches (six-subgroup partitioning: 0.36–0.68 to 4.75–5.67 mIU/L). For fT4, conventional (sex-based) and clustering (age-based) partitioning produced similar ranges (11.33–20.08 pmol/L), except reflimR’s notably lower limit (10.90 pmol/L). For fT3, conventional (age + sex) and clustering (age-only) partitioning showed comparable ranges (3.36–7.03 pmol/L), with clustering revealing a clearer age-related decline in the oldest group. Diagnostic performance varied markedly by analyte. TSH-only classification achieved positive discrimination across all 13 methods (Youden index: 0.173–0.239). In contrast, fT4-only and combined TSH + fT4 classifications performed at or below chance for most methods, with 75% of the cohort falling outside fT4 reference intervals, indicating an inter-platform harmonization issue rather than a partitioning failure. Decision curve analysis confirmed TSH-only classification’s superiority, exceeding universal testing from pt ≈ 0.20 onward across all methods. Conclusions: Age-stratified reference intervals combined with limit estimation showed potential diagnostic advantages over manufacturer and non-stratified intervals; however, an independent external validation using a clinically defined outcome indicated that this advantage was not consistently reproduced and was dependent on the clinical decision threshold considered. These results suggest that age stratification and algorithm choice merit further clinically adjudicated validation before broad clinical adoption, and that unsupervised clustering offers a practical, objective alternative to manual subgrouping for laboratories pursuing this approach. Full article

Background/Objectives: Endothelial dysfunction represents an early stage of vascular injury in type 2 diabetes mellitus (T2DM) and contributes to increased cardiovascular risk. Leptin, a hormone involved in metabolic and inflammatory regulation, has been implicated in vascular dysfunction. However, its association with digital thermal monitoring (DTM)-derived peripheral vascular reactivity in T2DM remains unclear. Methods: This cross-sectional study enrolled 88 patients with T2DM to investigate the association between serum leptin levels and peripheral vascular reactivity, assessed using the digital thermal monitoring-derived vascular reactivity index (VRI). Based on the VRI values, patients were categorized as having good (VRI ≥ 2.0), intermediate (VRI of 1.0–1.9), or poor (VRI < 1.0) vascular reactivity. Serum leptin levels were quantified using an enzyme immunoassay. Results: Patients with poor vascular reactivity were older and had higher total cholesterol, triglyceride, fasting glucose, glycated hemoglobin, urine albumin-to-creatinine ratio, and leptin levels. In the primary parsimonious multivariable logistic regression model adjusted for age, sex, body mass index (BMI) and eGFR, higher serum leptin levels were associated with vascular reactivity dysfunction. Linear regression analysis also showed that log-transformed leptin levels were negatively associated with VRI. Exploratory analyses, including poor vascular reactivity models and penalized regression models, showed generally consistent findings but were interpreted cautiously because of the limited number of outcome events. Conclusions: Higher serum leptin levels were associated with impaired DTM-derived peripheral vascular reactivity in clinically stable patients with T2DM after adjustment for age, sex, BMI, and eGFR. These findings should be interpreted cautiously and require validation in larger prospective studies. Full article

Background: Sexual function in postmenopausal women is influenced by both hormonal and psychological factors. This study investigates the associations between sex hormones, sexual function, and sexual beliefs in this population. Objective: This research seeks to assess the relationship between sex hormones, sexual function, and dysfunctional sexual beliefs in postmenopausal women. Methods: A cross-sectional study was conducted with 42 postmenopausal women aged 45–65 years. Instruments included the FSFI and SDBQ. Hormones assessed were testosterone, estradiol, progesterone, prolactin, DHEA, SHBG, and LH. Blood samples were collected in the morning and analyzed using chemiluminescence or radioimmunoassay. Pearson correlation tests were used, with Bonferroni adjustment applied to control for multiple comparisons. Results: Free testosterone was positively correlated with sexual desire and negatively associated with dysfunctional beliefs regarding sexual desire. Estradiol also showed a positive correlation with desire, while prolactin was negatively associated. No other FSFI domains showed significant hormonal associations. Conclusions: Findings suggest that testosterone may influence both sexual desire and the internalization of dysfunctional sexual beliefs in postmenopausal women, highlighting the interplay between biological and psychological dimensions of sexuality, which may be relevant for a more comprehensive clinical assessment of sexual function in this population. Full article

Objectives: The study aimed to assess (1) the prevalence of clinical obesity in a cohort of young Caucasian women with polyendocrine metabolic ovarian syndrome (PMOS), (2) estimate the cut-off value for triglyceride-glucose index—waist-to-height ratio (TyG-WHtR) and TyG—waist-to-hip ratio (TyG-WHR) indices discriminating the insulin resistance (IR) based on the HOMA-IR values and sex-hormone-binding-globulin (SHBG) levels, as well as (3) the occurrence of IR based on SHBG levels and HOMA-IR, TyG, TyG—body mass index (TyG-BMI), TyG—waist circumference (TyG-WC), TyG-WHtR, and TyG-WHR indices. Methods: This analysis included data retrieved from the medical records of 580 consecutive Caucasian women, for the first time, diagnosed with PMOS at the Gynecological Endocrinology Clinic, including anthropometric data, fasting glucose, insulin, and SHBG levels. Obesity and clinical obesity were diagnosed based on the WHO and LDEC criteria, respectively. The cut-off value for TyG-WHtR and TyG-WHR indices was calculated using receiver operating characteristic curve analysis. The occurrence of IR based on seven indices was assessed. Results: The prevalence of clinical obesity was 9.8% among women with BMI < 25 kg/m², 70.2% with BMI 25–29.9 kg/m², 100% with BMI > 30 kg/m². The empirical optimal cut-off values for the TyG-WHtR, corresponding to HOMA-IR ≥ 2.1 and SHBG ≤ 43.1 nmol/L, were 4.44 and 4.35, respectively, while for the TyG-WHR, 6.94 and 6.90, respectively. None of the IR indices identified all clinically obese women. SHBG cut-off was the marker that most frequently detected IR in both subgroups with and without clinical obesity. Conclusions: 1. The application of a new definition of clinical obesity increases the classification of obesity among women with PMOS. However, further studies are necessary to confirm the cut-off points for indirect anthropometric parameters of excess visceral fat based on DXA. 2. The cut-offs for the TyG-WHtR and TyG-WHR indices discriminating IR in young Caucasian women with PMOS were similar regardless of whether they were based on HOMA-IR and SHBG cut-offs. 3. SHBG concentration can be considered the most valuable marker for the diagnosis of IR in women with PMOS, both with and without clinical obesity. Full article

Background/Objectives: Korea has undergone rapid epidemiological transitions in cancer incidence over the past two decades. Using a 25-year nationwide dataset (1999–2023), we characterize long-term trends for 61 cancer types, examine inter-cancer correlations, and forecast incidence to 2028. Methods: Annual incidence counts, crude rates, and age-standardized incidence rates (ASIRs) stratified by sex were obtained from the Korea Central Cancer Registry (KCCR) via the Korean Statistical Information Service (KOSIS). Annual percent change (APC) was estimated using log-linear regression. Pearson correlation coefficients were computed among cancer-specific ASIRs, with false-discovery-rate (FDR) correction for multiple comparisons. Multiple and hierarchical regression evaluated the statistical association of individual cancer types with the overall cancer rate, and variance inflation factors (VIFs) were used to quantify multicollinearity. Time series forecasting used damped Holt–Winters exponential smoothing; forecast accuracy was assessed with rolling-origin cross-validation (RMSE, MAE, MAPE) and benchmarked against ARIMA. A sensitivity analysis excluding the pandemic years (2020–2021) tested the robustness of trend estimates. Five-year prevalence data (2007–2023) were analyzed from the KCCR prevalence module. Results: Total cancer incidence increased from 101,854 in 1999 to 288,613 in 2023, a 183% increase. The overall ASIR rose from 402.7 to 522.9 per 100,000 (2020 standard population). The three fastest-growing cancers were thyroid (APC +7.56%, p < 0.001), prostate (+6.98%, p < 0.001), and breast (+5.03%, p < 0.001). Stomach (APC −2.20%) and liver (−2.90%) cancers showed significant declines. Hierarchical regression showed that adding thyroid, breast, and prostate to lung and stomach increased explained variance from R² = 0.449 to 0.997; however, high VIF values (up to ~263) indicate substantial multicollinearity and compositional dependence, so these coefficients should not be read as independent causal contributions. Holt–Winters and ARIMA produced comparable accuracy (mean MAPE 4.6% vs. 4.7%). The five-year cancer prevalence pool reached 1,035,107 in 2023. Forecasting projects a total incidence of approximately 319,000 by 2028. Conclusions: Korean cancer epidemiology is undergoing a transition from infection-related cancers toward hormone-sensitive and screening-detectable malignancies. These findings support strategic resource allocation for high-growth cancers while maintaining vigilance over rising pancreatic and other emerging cancers. Full article

Sex- and gender-based immune differences have often been interpreted through a male–female biological binary, overlooking how endocrine signaling dynamically shapes immune function. Gender-affirming hormone therapy (GAHT) offers a unique physiological model to disentangle the effects of sex steroids from chromosomal background and examine immune plasticity in contexts relevant to reproductive health. This hormone-informed framework proposes that estradiol and testosterone regulate immune set-points across innate, adaptive, metabolic, and mucosal compartments. Through genomic and non-genomic signaling via androgen and estrogen receptors (AR, ERα/β), these hormones drive distinct immune outcomes: testosterone dampens type I interferon responses in plasmacytoid dendritic cells and reshapes monocyte inflammatory profiles, while estradiol promotes macrophage polarization and enhances T helper1 (Th1) responses. Hormonal effects are closely coupled to cellular metabolism: androgen signaling acts as a “metabolic brake” on Th17 cells by limiting glutaminolysis, a process reinforced by epigenetic remodeling, and is reflected in shifts in the circulating metabolome, positioning metabolomics as a sensitive tool for monitoring hormone-driven immune adaptation. Regardless, hormones also reshape mucosal barriers and reproductive microbiome composition. GAHT alters vaginal and gut microbial communities and their metabolism, influencing mucosal immunity, local inflammation, and reproductive tract homeostasis, with potential implications for fertility preservation, susceptibility to reproductive tract infections, and long-term genital mucosal health. Collectively, this evidence underscores that human immunity is highly responsive to endocrine context. This review synthesizes evidence linking endocrine trajectories, tissue microenvironments, reproductive biology, and social determinants of health, aiming to advance understanding of immune plasticity and contribute to a more inclusive framework of human immune diversity. Full article

Early sex identification is essential for the propagation, cultivation, quality improvement, and germplasm management of dioecious horticultural plants and related functionally dioecious systems, particularly in perennial species with long juvenile phases. However, the reliability and transferability of sex-identification technologies depend strongly on the underlying sex-determining mechanism. Here, we synthesize recent advances in plant sex determination and diagnostic technologies, ranging from morphological and biochemical traits to molecular markers, high-throughput sequencing, structural-variant detection, and emerging non-invasive phenotyping. We propose that sex-identification strategies should be selected according to the biological target generated by each mechanism, including heteromorphic sex chromosomes, homomorphic sex-determining regions (SDRs), functional sex-determining genes, sex chromosome turnover, dosage-dependent systems, and environmentally labile sex expression. We further distinguish genetic, developmental, physiological, and phenotypic layers of plant sex, emphasizing that DNA markers and spectral phenotyping provide complementary information. Genomic markers and non-invasive phenotyping are expected to be consistent when genetic sex is stably expressed, but they may become inconsistent when sex expression is developmentally, hormonally, or environmentally modulated. While molecular markers remain the most reliable tools for confirmatory genotyping, Raman spectroscopy, surface-enhanced Raman scattering (SERS), hyperspectral imaging, and machine learning may serve as rapid prescreening tools in large breeding populations, although their application remains at the proof-of-concept stage. Finally, we present a mechanism-guided decision framework for integrating genomic markers and non-invasive phenotyping to support early sex screening, propagation planning, planting-material optimization, and marker-assisted improvement in dioecious horticultural plants. Full article