Pub Date : 2026-01-23DOI: 10.1186/s13293-026-00829-5
Yizhou Wang, Priyanka Bhandary, Jason H Moore, Xue Li, Zhiping Wang
Background: Bladder cancer affects men and women differently: men are diagnosed more frequently, but women often present with advanced disease and have worse survival. The biological mechanisms underlying these disparities remain unclear. This study aimed to identify sex-specific molecular features and regulatory interactions that shape tumor biology and outcomes.
Methods: We performed an integrative multi-omics analysis combining bulk messenger RNA and microRNA expression, survival modeling, and single-cell transcriptomic profiling. Data were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and the Genome Sequence Archive. Differential expression analyses were conducted separately in tumors and in normal samples to compare males and females. Experimentally validated microRNA-mRNA target pairs were tested for correlation, and survival associations were evaluated using Kaplan-Meier and Cox models. Single-cell RNA-seq data were analyzed to assess sex-biased expression across tumor and immune cell populations.
Results: We identified 48 tumor-specific sex-biased microRNAs and 456 tumor-specific sex-biased genes, the majority located on autosomes rather than sex chromosomes. Correlation analysis revealed 82 experimentally supported, negatively correlated microRNA-mRNA pairs, including 63 discordant pairs with opposite sex-biased expression, suggesting sex-specific regulatory interactions. Several of these features were significantly associated with overall survival in a sex-dependent manner. For example, the male-upregulated microRNA miR-1270 showed repression of the female-biased targets CYP26B1 and FAM180A, both of which were associated with poor survival, highlighting potential prognostic and therapeutic relevance. Single-cell analysis revealed widespread sex-biased expression across epithelial, stromal, and immune cells, with female tumors showing stronger signals in stromal and immune compartments, which may contribute to the more aggressive clinical course observed in females.
Conclusions: Our findings indicate that sex disparities in bladder cancer are largely driven by post-transcriptional regulation of autosomal genes, rather than sex chromosome dosage. By linking sex-biased microRNAs, target genes, and patient survival with cell type-specific expression, this study provides new insight into the biological basis of sex differences in bladder cancer. These results underscore the importance of incorporating sex as a critical variable in biomarker development, therapeutic targeting, and clinical trial design.
{"title":"Integrative microRNA and transcriptome analysis reveals sex-specific molecular divergence in human bladder cancer.","authors":"Yizhou Wang, Priyanka Bhandary, Jason H Moore, Xue Li, Zhiping Wang","doi":"10.1186/s13293-026-00829-5","DOIUrl":"10.1186/s13293-026-00829-5","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer affects men and women differently: men are diagnosed more frequently, but women often present with advanced disease and have worse survival. The biological mechanisms underlying these disparities remain unclear. This study aimed to identify sex-specific molecular features and regulatory interactions that shape tumor biology and outcomes.</p><p><strong>Methods: </strong>We performed an integrative multi-omics analysis combining bulk messenger RNA and microRNA expression, survival modeling, and single-cell transcriptomic profiling. Data were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and the Genome Sequence Archive. Differential expression analyses were conducted separately in tumors and in normal samples to compare males and females. Experimentally validated microRNA-mRNA target pairs were tested for correlation, and survival associations were evaluated using Kaplan-Meier and Cox models. Single-cell RNA-seq data were analyzed to assess sex-biased expression across tumor and immune cell populations.</p><p><strong>Results: </strong>We identified 48 tumor-specific sex-biased microRNAs and 456 tumor-specific sex-biased genes, the majority located on autosomes rather than sex chromosomes. Correlation analysis revealed 82 experimentally supported, negatively correlated microRNA-mRNA pairs, including 63 discordant pairs with opposite sex-biased expression, suggesting sex-specific regulatory interactions. Several of these features were significantly associated with overall survival in a sex-dependent manner. For example, the male-upregulated microRNA miR-1270 showed repression of the female-biased targets CYP26B1 and FAM180A, both of which were associated with poor survival, highlighting potential prognostic and therapeutic relevance. Single-cell analysis revealed widespread sex-biased expression across epithelial, stromal, and immune cells, with female tumors showing stronger signals in stromal and immune compartments, which may contribute to the more aggressive clinical course observed in females.</p><p><strong>Conclusions: </strong>Our findings indicate that sex disparities in bladder cancer are largely driven by post-transcriptional regulation of autosomal genes, rather than sex chromosome dosage. By linking sex-biased microRNAs, target genes, and patient survival with cell type-specific expression, this study provides new insight into the biological basis of sex differences in bladder cancer. These results underscore the importance of incorporating sex as a critical variable in biomarker development, therapeutic targeting, and clinical trial design.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"29"},"PeriodicalIF":5.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12911049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1186/s13293-025-00819-z
Yujia Li, Jialing Xie, Jie Chen, Xiaofei Huo, Meng Wang, Tao Hu, Manfei Deng, Wenyu Cao, Yang Xu
<p><strong>Background: </strong>Sex differences in brain function critically influence vulnerability to stress-related disorders such as anxiety and depression. Stress relief, defined as a positive emotional state following the termination of a threat, has been proposed as a natural reward promoting resilience. However, little is known about sex differences in stress relief behavior and the underlying neural mechanisms involved.</p><p><strong>Methods: </strong>Adult male and female C57BL/6J mice were subjected to a conditioned place preference (CPP) paradigm to evaluate stress relief responses following acute restraint stress. Estrous cycle stages in females were monitored during the test day to exclude hormonal effects. Whole-brain neuronal activity was assessed using large-scale c-Fos mapping to identify sex-specific neural correlates of stress relief. To establish causality, chemogenetic manipulations were performed by bilaterally expressing hM3Dq or hM4Di DREADDs in the central amygdala (CeA), followed by clozapine-N-oxide administration to selectively activate or inhibit CeA neurons during the behavioral test.</p><p><strong>Results: </strong>We found that male mice exhibited a robust stress relief response, whereas female mice failed to display stress relief, independent of stress intensity or the estrous cycle. c-Fos mapping revealed CeA neuronal inactivation in males but not females during stress relief. Chemogenetic activation of CeA neurons abolished stress relief in males, whereas inhibition of CeA neurons facilitated stress relief in females.</p><p><strong>Conclusions: </strong>These data highlight the sex-specific role of CeA neurons in regulating stress relief, with inactivation promoting relief in males and inhibition enabling relief in females. These findings may provide a neural basis for understanding sex-specific mechanisms of stress relief and offer insights into the circuit-level origins of sex-biased vulnerability to stress-related psychiatric disorders.</p><p><strong>Highlights: </strong>Male mice exhibited robust stress relief responses, whereas females failed to display stress relief. The absence of stress relief in females was independent of stress intensity and estrous cycle stage. Whole-brain c-Fos mapping revealed sex-specific neural activation patterns, with CeA neurons inactivated in males but not in females during stress relief. Chemogenetic activation of CeA neurons abolished stress relief in males, whereas inhibition of CeA neurons enabled stress relief in females. Exploring sex differences in the brain is important for understanding the effects of such differences in stress-related disorders characterized by sex bias, as well as their therapeutic implications. In this manuscript, we examined sex differences in stress relief, a positive emotion triggered by the absence of an expected threat or the termination of an ongoing threat, as well as its potential mechanism. Our findings revealed sex variation in the stres
背景：脑功能的性别差异对焦虑和抑郁等压力相关疾病的易感性有重要影响。压力缓解被定义为威胁结束后的积极情绪状态，被认为是一种促进恢复力的自然奖励。然而，人们对压力缓解行为的性别差异以及所涉及的潜在神经机制知之甚少。方法：采用条件位置偏好（CPP）模式评价成年雄性和雌性C57BL/6J小鼠急性约束应激后的应激缓解反应。在测试期间，对雌性动物的发情周期进行监测，以排除激素的影响。使用大规模c-Fos图谱评估全脑神经元活动，以确定压力缓解的性别特异性神经相关性。为了确定因果关系，通过在中央杏仁核（CeA）中双侧表达hM3Dq或hM4Di DREADDs，然后在行为测试中给予氯氮平- n -氧化物选择性激活或抑制CeA神经元，进行化学发生操作。结果：我们发现雄性小鼠表现出强烈的应激缓解反应，而雌性小鼠没有表现出应激缓解，这与应激强度或发情周期无关。c-Fos图谱显示，在应激缓解过程中，雄性CeA神经元失活，而雌性没有。CeA神经元的化学发生激活在雄性小鼠中消除了应激缓解，而CeA神经元的抑制在雌性小鼠中促进了应激缓解。结论：这些数据强调了CeA神经元在调节应激缓解中的性别特异性作用，失活促进雄性缓解，抑制使雌性缓解。这些发现可能为理解压力缓解的性别特异性机制提供了神经基础，并提供了对压力相关精神疾病的性别偏见易感性的回路水平起源的见解。重点：雄性小鼠表现出强烈的应激缓解反应，而雌性小鼠没有表现出应激缓解反应。雌性无应激释放与应激强度和发情周期无关。全脑c-Fos图谱揭示了性别特异性的神经激活模式，在压力缓解期间，雄性CeA神经元失活，而雌性则没有。CeA神经元的化学发生激活在雄性中消除了应激缓解，而CeA神经元的抑制在雌性中则使应激缓解。探索大脑中的性别差异对于理解以性别偏见为特征的压力相关疾病的这种差异的影响及其治疗意义非常重要。在这篇文章中，我们研究了压力缓解的性别差异，压力缓解是一种由预期威胁的缺失或持续威胁的终止引发的积极情绪，以及它的潜在机制。我们的研究结果揭示了压力缓解反应的性别差异，因为雌性小鼠没有表现出压力缓解反应，这与压力强度或发情周期波动无关。通过在应激缓解实验后测定小鼠大脑中的神经元激活，我们发现在这种模式下，雄性小鼠的CeA神经元失活，而雌性小鼠则没有。此外，CeA神经元的化学发生激活消除了雄性小鼠的应激缓解反应，而CeA神经元的化学发生失活促进了雌性小鼠的应激缓解反应。我们推测CeA神经元可能在小鼠两性二态应激缓解反应中起关键作用。因此，在临床前和临床研究中考虑性别差异是很重要的，这些研究试图了解与压力缓解相关的机制。
{"title":"Involvement of the central amygdaloid nucleus in the regulation of sex differences in the stress relief response in mice.","authors":"Yujia Li, Jialing Xie, Jie Chen, Xiaofei Huo, Meng Wang, Tao Hu, Manfei Deng, Wenyu Cao, Yang Xu","doi":"10.1186/s13293-025-00819-z","DOIUrl":"10.1186/s13293-025-00819-z","url":null,"abstract":"<p><strong>Background: </strong>Sex differences in brain function critically influence vulnerability to stress-related disorders such as anxiety and depression. Stress relief, defined as a positive emotional state following the termination of a threat, has been proposed as a natural reward promoting resilience. However, little is known about sex differences in stress relief behavior and the underlying neural mechanisms involved.</p><p><strong>Methods: </strong>Adult male and female C57BL/6J mice were subjected to a conditioned place preference (CPP) paradigm to evaluate stress relief responses following acute restraint stress. Estrous cycle stages in females were monitored during the test day to exclude hormonal effects. Whole-brain neuronal activity was assessed using large-scale c-Fos mapping to identify sex-specific neural correlates of stress relief. To establish causality, chemogenetic manipulations were performed by bilaterally expressing hM3Dq or hM4Di DREADDs in the central amygdala (CeA), followed by clozapine-N-oxide administration to selectively activate or inhibit CeA neurons during the behavioral test.</p><p><strong>Results: </strong>We found that male mice exhibited a robust stress relief response, whereas female mice failed to display stress relief, independent of stress intensity or the estrous cycle. c-Fos mapping revealed CeA neuronal inactivation in males but not females during stress relief. Chemogenetic activation of CeA neurons abolished stress relief in males, whereas inhibition of CeA neurons facilitated stress relief in females.</p><p><strong>Conclusions: </strong>These data highlight the sex-specific role of CeA neurons in regulating stress relief, with inactivation promoting relief in males and inhibition enabling relief in females. These findings may provide a neural basis for understanding sex-specific mechanisms of stress relief and offer insights into the circuit-level origins of sex-biased vulnerability to stress-related psychiatric disorders.</p><p><strong>Highlights: </strong>Male mice exhibited robust stress relief responses, whereas females failed to display stress relief. The absence of stress relief in females was independent of stress intensity and estrous cycle stage. Whole-brain c-Fos mapping revealed sex-specific neural activation patterns, with CeA neurons inactivated in males but not in females during stress relief. Chemogenetic activation of CeA neurons abolished stress relief in males, whereas inhibition of CeA neurons enabled stress relief in females. Exploring sex differences in the brain is important for understanding the effects of such differences in stress-related disorders characterized by sex bias, as well as their therapeutic implications. In this manuscript, we examined sex differences in stress relief, a positive emotion triggered by the absence of an expected threat or the termination of an ongoing threat, as well as its potential mechanism. Our findings revealed sex variation in the stres","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"27"},"PeriodicalIF":5.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12892754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1186/s13293-025-00820-6
Erin E Sundermann, Sarah J Banks, Mark W Bondi, Maricedes Acosta Martinez, Anat Biegon, Lindsay J Rotblatt, Thomas Hildebrandt
Background: Alzheimer's disease (AD) exhibits sex differences in pathology and cognitive trajectories. Understanding how these differences manifest across the Alzheimer's continuum can improve early detection, diagnostics, and interventions. We examined sex differences in the association between cerebrospinal fluid (CSF) pTau181/Aβ42 ratio changes and verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD.
Methods: In this retrospective, longitudinal, observational study, data were extracted from 401 participants (age range: 55-87.8, 98% non-Hispanic White) of the Alzheimer's Disease Neuroimaging Initiative cohort study who were classified as either preclinical AD (78 females, 73 males) or MCI (104 females, 146 males) at baseline and had CSF pTau181/Aβ42 ratio and cognitive assessment data at at-least two timepoints. Using regression models, we examined the relationship between changes in CSF pTau181/Aβ42 and verbal memory across all available time points and the moderating role of sex and AD stage over a mean follow-up period of 4 years. Verbal memory was represented by a composite z-score averaging Learning and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype.
Results: A significant sex * diagnostic group * biomarker change interaction (b=-17.47, 95%CI = 27.60 to -7.33, p = .001) indicated that sex differences in the relationship between changes in CSF pTau181/Aβ42 ratio and verbal memory differed by disease stage. While males in the preclinical AD stage showed steeper memory decline than females with increasing pTau181/Aβ42 ratios, this difference was not statistically significant. In contrast, in the MCI stage, a significant sex * biomarker change interaction (b = 10.17, 95% CI = 4.94 to 15.40, p < .001) indicated that females exhibited significantly steeper memory decline associated with increasing pTau181/Aβ42 ratios compared to males.
Conclusion: Sex differences in the relationship between AD biomarker levels and cognitive decline vary by disease stage. Although not statistically significant, females demonstrated resilience to memory decline in the preclinical stage, whereas, in the MCI stage, they experienced significantly steeper memory loss compared to males. Results suggest that accounting for sex in biomarker-based methods of disease detection and tracking can improve early detection and intervention in both sexes.
背景：阿尔茨海默病（AD）在病理和认知轨迹上表现出性别差异。了解这些差异是如何在阿尔茨海默病的连续体中表现出来的，可以改善早期发现、诊断和干预。我们研究了阿尔茨海默病临床前和轻度认知障碍（MCI）阶段脑脊液（CSF） pTau181/ a - β42比值变化与言语记忆下降之间关系的性别差异。方法：在这项回顾性、纵向、观察性研究中，从阿尔茨海默病神经影像学计划队列研究的401名参与者（年龄范围：55-87.8岁，98%非西班牙裔白人）中提取数据，这些参与者在基线时被分类为临床前AD（78名女性，73名男性）或MCI（104名女性，146名男性），并且至少有两个时间点的CSF pTau181/ a - β42比和认知评估数据。使用回归模型，我们检查了脑脊液pTau181/ a - β42在所有可用时间点与言语记忆的变化之间的关系，以及性别和AD分期在平均4年随访期间的调节作用。言语记忆用雷伊听觉言语学习测验的学习和延迟回忆z分数的平均z分数表示。协变量包括基线年龄、教育程度和载脂蛋白E基因型。结果：性别*诊断组*生物标志物改变交互作用显著(b=-17.47, 95%CI = 27.60 ~ -7.33, p =。0.001)表明脑脊液pTau181/ a - β42比值变化与言语记忆的关系因疾病分期而异。虽然临床前AD阶段的男性比女性表现出更急剧的记忆衰退，但pTau181/ a - β42比值升高，这种差异无统计学意义。相反，在MCI阶段，性别与生物标志物变化之间存在显著的相互作用（b = 10.17, 95% CI = 4.94 ~ 15.40, p）。结论：AD生物标志物水平与认知能力下降关系的性别差异因疾病阶段而异。虽然没有统计学上的显著性，但女性在临床前阶段表现出对记忆衰退的恢复能力，而在轻度认知障碍阶段，她们的记忆衰退明显比男性严重。结果表明，在基于生物标志物的疾病检测和跟踪方法中考虑性别可以改善两性的早期发现和干预。
{"title":"Sex differences in the relationship of biomarker change to memory decline in early Alzheimer's disease: an observational cohort study.","authors":"Erin E Sundermann, Sarah J Banks, Mark W Bondi, Maricedes Acosta Martinez, Anat Biegon, Lindsay J Rotblatt, Thomas Hildebrandt","doi":"10.1186/s13293-025-00820-6","DOIUrl":"10.1186/s13293-025-00820-6","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) exhibits sex differences in pathology and cognitive trajectories. Understanding how these differences manifest across the Alzheimer's continuum can improve early detection, diagnostics, and interventions. We examined sex differences in the association between cerebrospinal fluid (CSF) pTau181/Aβ42 ratio changes and verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD.</p><p><strong>Methods: </strong>In this retrospective, longitudinal, observational study, data were extracted from 401 participants (age range: 55-87.8, 98% non-Hispanic White) of the Alzheimer's Disease Neuroimaging Initiative cohort study who were classified as either preclinical AD (78 females, 73 males) or MCI (104 females, 146 males) at baseline and had CSF pTau181/Aβ42 ratio and cognitive assessment data at at-least two timepoints. Using regression models, we examined the relationship between changes in CSF pTau181/Aβ42 and verbal memory across all available time points and the moderating role of sex and AD stage over a mean follow-up period of 4 years. Verbal memory was represented by a composite z-score averaging Learning and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype.</p><p><strong>Results: </strong>A significant sex * diagnostic group * biomarker change interaction (b=-17.47, 95%CI = 27.60 to -7.33, p = .001) indicated that sex differences in the relationship between changes in CSF pTau181/Aβ42 ratio and verbal memory differed by disease stage. While males in the preclinical AD stage showed steeper memory decline than females with increasing pTau181/Aβ42 ratios, this difference was not statistically significant. In contrast, in the MCI stage, a significant sex * biomarker change interaction (b = 10.17, 95% CI = 4.94 to 15.40, p < .001) indicated that females exhibited significantly steeper memory decline associated with increasing pTau181/Aβ42 ratios compared to males.</p><p><strong>Conclusion: </strong>Sex differences in the relationship between AD biomarker levels and cognitive decline vary by disease stage. Although not statistically significant, females demonstrated resilience to memory decline in the preclinical stage, whereas, in the MCI stage, they experienced significantly steeper memory loss compared to males. Results suggest that accounting for sex in biomarker-based methods of disease detection and tracking can improve early detection and intervention in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12930658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1186/s13293-026-00823-x
Wan Wang, Man Huang, Wu-Lin Li, Xiao-Wei Du, Yue Li, Zhao-Hui Lu, Bei-Bei Sun, Yu-Qing Mao, Xiao-Ya Ma, Xiao Han, Xiao Wu, Hui Chen, Fei Wang
Background and aims: Obesity is usually linked to negative outcomes in many diseases; however, some acute critical conditions exhibit a phenomenon known as the obesity paradox. This investigation assessed sex-specific differences in type 2 myocardial infarction (T2MI), a condition caused by an imbalance between oxygen supply and demand in the myocardium and unrelated to atherosclerotic plaque rupture. Additionally, the study explored the implications of body mass index (BMI) in patients with acute ischemic stroke (AIS).
Methods: AIS patients were consecutively enrolled at Jiading District Central Hospital affiliated Shanghai University of Medicine & Health Sciences, from October 1, 2017, to December 31, 2023. Participants were divided into four groups based on their BMI: underweight group, normal weight group, overweight group, and obesity group. The primary outcome of the study was the incidence of T2MI. We employed Cox regression analysis and Kaplan-Meier curves to examine the relationship between BMI and the occurrence of T2MI. Additionally, we performed a restricted cubic spline (RCS) analysis to evaluate the linearity of this relationship, utilizing an iterative algorithm to pinpoint inflection points. The subgroup forest plot displays how the four BMI groups vary across different layers.
Results: The incidence of T2MI was 4.43%(131/2995) in AIS patients. After adjusting for potential confounding variables, the risk of T2MI was higher in the normal-weight group (HR, 2.11; 95% CI, 1.36-3.26; p < 0.001) compared to the obese group. In female patients, the risk of T2MI was higher in both the normal-weight group (HR, 3.47; 95% CI, 1.64-7.36; P = 0.001) and the underweight group (HR, 4.06; 95% CI, 1.44-11.44; P = 0.008) compared to the obese group; however, no such association was found in male patients. Furthermore, the RCS analysis confirmed a linear correlation between BMI and the risk of T2MI.
Conclusions: The association between BMI and T2MI in AIS patients varied between genders. Obese female AIS patients had a lower risk of T2MI, a trend that was not mirrored in their male counterparts. These findings underscore the importance of considering sex-specific factors in understanding the complex relationship between obesity and T2MI in patients with AIS.
{"title":"Sex-specific obesity paradox and type 2 myocardial infarction in acute ischemic stroke (AIS) patients.","authors":"Wan Wang, Man Huang, Wu-Lin Li, Xiao-Wei Du, Yue Li, Zhao-Hui Lu, Bei-Bei Sun, Yu-Qing Mao, Xiao-Ya Ma, Xiao Han, Xiao Wu, Hui Chen, Fei Wang","doi":"10.1186/s13293-026-00823-x","DOIUrl":"10.1186/s13293-026-00823-x","url":null,"abstract":"<p><strong>Background and aims: </strong>Obesity is usually linked to negative outcomes in many diseases; however, some acute critical conditions exhibit a phenomenon known as the obesity paradox. This investigation assessed sex-specific differences in type 2 myocardial infarction (T2MI), a condition caused by an imbalance between oxygen supply and demand in the myocardium and unrelated to atherosclerotic plaque rupture. Additionally, the study explored the implications of body mass index (BMI) in patients with acute ischemic stroke (AIS).</p><p><strong>Methods: </strong>AIS patients were consecutively enrolled at Jiading District Central Hospital affiliated Shanghai University of Medicine & Health Sciences, from October 1, 2017, to December 31, 2023. Participants were divided into four groups based on their BMI: underweight group, normal weight group, overweight group, and obesity group. The primary outcome of the study was the incidence of T2MI. We employed Cox regression analysis and Kaplan-Meier curves to examine the relationship between BMI and the occurrence of T2MI. Additionally, we performed a restricted cubic spline (RCS) analysis to evaluate the linearity of this relationship, utilizing an iterative algorithm to pinpoint inflection points. The subgroup forest plot displays how the four BMI groups vary across different layers.</p><p><strong>Results: </strong>The incidence of T2MI was 4.43%(131/2995) in AIS patients. After adjusting for potential confounding variables, the risk of T2MI was higher in the normal-weight group (HR, 2.11; 95% CI, 1.36-3.26; p < 0.001) compared to the obese group. In female patients, the risk of T2MI was higher in both the normal-weight group (HR, 3.47; 95% CI, 1.64-7.36; P = 0.001) and the underweight group (HR, 4.06; 95% CI, 1.44-11.44; P = 0.008) compared to the obese group; however, no such association was found in male patients. Furthermore, the RCS analysis confirmed a linear correlation between BMI and the risk of T2MI.</p><p><strong>Conclusions: </strong>The association between BMI and T2MI in AIS patients varied between genders. Obese female AIS patients had a lower risk of T2MI, a trend that was not mirrored in their male counterparts. These findings underscore the importance of considering sex-specific factors in understanding the complex relationship between obesity and T2MI in patients with AIS.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"26"},"PeriodicalIF":5.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12892716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: To assess the impact of sex on mortality and malignancy in patients with primary Sjögren's disease (pSD).
Methods: This ambispective cohort study included 1,182 pSD patients (1,025 women and 157 men) from the China-Japan Friendship Hospital between 2014-2023 and followed through 2024. Survival outcomes were estimated via Kaplan-Meier curves, and SMRs were calculated. Independent risk factors were identified via multivariate Cox regression, followed by stepwise Cox, sex-stratified and interaction analyses.
Results: During follow-up, 125 deaths (10.6%) and 33 malignancies (2.8%) occurred, both of which were more common in men (log-rank tests, P < 0.001). Overall mortality was markedly higher in men (25.5%, SMR = 4.79) than in women (8.3%, SMR = 2.42). Male sex was independently associated with higher risk of mortality (HR = 1.998, P = 0.004) and cancer incidence (HR = 3.799, P = 0.001). Sex-stratified analyses revealed distinct death-associated factors: interstitial lung disease (ILD), pulmonary infection and ischemic stroke were independently associated with mortality in men, whereas older age, low C3, elevated C-reactive protein and total bilirubin (TBIL) levels were associated with mortality in women. With respect to cancer, longer disease duration, lymphadenopathy, lymphocytopenia, elevated TBIL and hypochloremia were independently associated with cancer risk in women, whereas no variables showed an independent association with cancer risk among men. Interaction analyses demonstrated additive interactions between male sex and elevated ESSDAI scores, as well as male sex and concomitant ILD, in relation to mortality.
Conclusion: Compared with women, men with pSD presented greater risks and distinct risk profiles of death and malignancy. Moreover, male sex was independently associated with adverse outcomes and acted as an important effect modifier, highlighting the need for sex-specific risk stratification and clinical management.
Trial registration: This ambispective cohort study was registered in the Clinical Trial Registry (ID: NCT06528197) on June 27, 2024 and conducted in accordance with the Declaration of Helsinki.
{"title":"Sex differences in primary Sjögren's disease: prognostic impact on mortality and cancer.","authors":"Chunxin Lei, Xiya Zhang, Yan Zhang, Yunlong Fang, Jiaqi Chen, Zihan Liu, Xuanyi Zhou, Bojie Tang, Jiahe Liao, Ziwei Huang, Jianying Yang, Zihan Wang, Ting Liu, Qingwen Tao, Jing Luo","doi":"10.1186/s13293-026-00827-7","DOIUrl":"10.1186/s13293-026-00827-7","url":null,"abstract":"<p><strong>Objective: </strong>To assess the impact of sex on mortality and malignancy in patients with primary Sjögren's disease (pSD).</p><p><strong>Methods: </strong>This ambispective cohort study included 1,182 pSD patients (1,025 women and 157 men) from the China-Japan Friendship Hospital between 2014-2023 and followed through 2024. Survival outcomes were estimated via Kaplan-Meier curves, and SMRs were calculated. Independent risk factors were identified via multivariate Cox regression, followed by stepwise Cox, sex-stratified and interaction analyses.</p><p><strong>Results: </strong>During follow-up, 125 deaths (10.6%) and 33 malignancies (2.8%) occurred, both of which were more common in men (log-rank tests, P < 0.001). Overall mortality was markedly higher in men (25.5%, SMR = 4.79) than in women (8.3%, SMR = 2.42). Male sex was independently associated with higher risk of mortality (HR = 1.998, P = 0.004) and cancer incidence (HR = 3.799, P = 0.001). Sex-stratified analyses revealed distinct death-associated factors: interstitial lung disease (ILD), pulmonary infection and ischemic stroke were independently associated with mortality in men, whereas older age, low C3, elevated C-reactive protein and total bilirubin (TBIL) levels were associated with mortality in women. With respect to cancer, longer disease duration, lymphadenopathy, lymphocytopenia, elevated TBIL and hypochloremia were independently associated with cancer risk in women, whereas no variables showed an independent association with cancer risk among men. Interaction analyses demonstrated additive interactions between male sex and elevated ESSDAI scores, as well as male sex and concomitant ILD, in relation to mortality.</p><p><strong>Conclusion: </strong>Compared with women, men with pSD presented greater risks and distinct risk profiles of death and malignancy. Moreover, male sex was independently associated with adverse outcomes and acted as an important effect modifier, highlighting the need for sex-specific risk stratification and clinical management.</p><p><strong>Trial registration: </strong>This ambispective cohort study was registered in the Clinical Trial Registry (ID: NCT06528197) on June 27, 2024 and conducted in accordance with the Declaration of Helsinki.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"25"},"PeriodicalIF":5.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12888568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1186/s13293-025-00821-5
Beini Zhou, Yixuan Wang, Yuhan Wang, Jingyi Zhang, Qingfeng Zhang, Ke Hu
Background: The relationship between obstructive sleep apnea (OSA) and thyroid hormone sensitivity remains unclear. Thyroid hormone sensitivity indices may reveal subclinical hypothalamic-pituitary-thyroid (HPT) axis dysregulation beyond conventional hormone levels.
Methods: We analyzed 718 euthyroid adults who underwent overnight sleep monitoring, using thyroid‑stimulating hormone index (TSHI), thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyrotroph T4 resistance index (TT4RI), thyrotroph T3 resistance index (TT3RI) and the ratio of free triiodothyronine to free thyroxine (FT3/FT4 ratio) to assess central and peripheral thyroid hormone sensitivity. Analysis of covariance assessed differences across OSA severity after adjusting for age and BMI. Multivariable linear regression examined associations between OSA severity and thyroid hormone sensitivity indices in sex-stratified models. Correlations between OSA-related parameters and thyroid hormones sensitivity indices were further explored using quadratic prediction plots.
Results: Among females, OSA patients showed higher FT4 and significantly increased TFQI, PTFQI, TSHI, and TT4RI, but lower FT3/FT4 ratio compared with non-OSA. TFQI (P for trend = 0.0395) and TT4RI (P for trend = 0.0293) were positively correlated with increasing OSA severity. OSA was independently associated with elevated TFQI (β = 0.26, 95% CI 0.010-0.42, P = 0.001), PTFQI (β = 0.20, 95% CI 0.05-0.35, P = 0.011), TSHI (β = 0.24, 95% CI 0.03-0.44, P = 0.025), and TT4RI (β = 6.82, 95% CI 0.59-13.05, P = 0.033). apnea-hypopnea index (AHI), oxygen desaturation index (ODI) were significantly correlated with TT4RI (P = 0.034, 0.021, respectively). No significant associations were observed in males.
Conclusions: OSA is associated with impaired central and peripheral thyroid hormone sensitivity in euthyroid females, but not in males.
背景：阻塞性睡眠呼吸暂停（OSA）与甲状腺激素敏感性之间的关系尚不清楚。甲状腺激素敏感性指标可能显示亚临床下丘脑-垂体-甲状腺（HPT）轴的失调超出常规激素水平。方法：采用促甲状腺激素指数（TSHI）、甲状腺反馈分位数指数（TFQI）、参数甲状腺反馈分位数指数（PTFQI）、促甲状腺素T4抵抗指数（TT4RI）、促甲状腺素T3抵抗指数（TT3RI）和游离三碘甲状腺原氨酸与游离甲状腺素之比（FT3/FT4比）对718例正常甲状腺激素进行夜间睡眠监测，评估其中枢和外周甲状腺激素敏感性。协方差分析评估了调整年龄和BMI后OSA严重程度的差异。在性别分层模型中，多变量线性回归检验了OSA严重程度与甲状腺激素敏感性指数之间的关系。利用二次预测图进一步探讨osa相关参数与甲状腺激素敏感性指标的相关性。结果：女性OSA患者FT4较高，TFQI、PTFQI、TSHI、TT4RI明显升高，FT3/FT4比值低于非OSA患者。TFQI （P趋势= 0.0395）、TT4RI （P趋势= 0.0293）与OSA严重程度加重呈正相关。阻塞性睡眠呼吸暂停综合症是独立与高架TFQI(β= 0.26,95% CI 0.010 - -0.42, P = 0.001), PTFQI(β= 0.20,95% CI 0.05 - -0.35, P = 0.011), TSHI(β= 0.24,95% CI 0.03 - -0.44, P = 0.025),和TT4RI(β= 6.82,95% CI 0.59 - -13.05, P = 0.033)。呼吸暂停低通气指数（AHI）、氧去饱和指数（ODI）与TT4RI呈显著相关（P分别为0.034、0.021）。在男性中没有观察到显著的关联。结论：OSA与甲状腺功能正常的女性中枢和外周甲状腺激素敏感性受损有关，而与男性无关。
{"title":"Sex-specific associations between obstructive sleep apnea and thyroid hormone sensitivity in euthyroid adults.","authors":"Beini Zhou, Yixuan Wang, Yuhan Wang, Jingyi Zhang, Qingfeng Zhang, Ke Hu","doi":"10.1186/s13293-025-00821-5","DOIUrl":"10.1186/s13293-025-00821-5","url":null,"abstract":"<p><strong>Background: </strong>The relationship between obstructive sleep apnea (OSA) and thyroid hormone sensitivity remains unclear. Thyroid hormone sensitivity indices may reveal subclinical hypothalamic-pituitary-thyroid (HPT) axis dysregulation beyond conventional hormone levels.</p><p><strong>Methods: </strong>We analyzed 718 euthyroid adults who underwent overnight sleep monitoring, using thyroid‑stimulating hormone index (TSHI), thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyrotroph T4 resistance index (TT4RI), thyrotroph T3 resistance index (TT3RI) and the ratio of free triiodothyronine to free thyroxine (FT3/FT4 ratio) to assess central and peripheral thyroid hormone sensitivity. Analysis of covariance assessed differences across OSA severity after adjusting for age and BMI. Multivariable linear regression examined associations between OSA severity and thyroid hormone sensitivity indices in sex-stratified models. Correlations between OSA-related parameters and thyroid hormones sensitivity indices were further explored using quadratic prediction plots.</p><p><strong>Results: </strong>Among females, OSA patients showed higher FT4 and significantly increased TFQI, PTFQI, TSHI, and TT4RI, but lower FT3/FT4 ratio compared with non-OSA. TFQI (P for trend = 0.0395) and TT4RI (P for trend = 0.0293) were positively correlated with increasing OSA severity. OSA was independently associated with elevated TFQI (β = 0.26, 95% CI 0.010-0.42, P = 0.001), PTFQI (β = 0.20, 95% CI 0.05-0.35, P = 0.011), TSHI (β = 0.24, 95% CI 0.03-0.44, P = 0.025), and TT4RI (β = 6.82, 95% CI 0.59-13.05, P = 0.033). apnea-hypopnea index (AHI), oxygen desaturation index (ODI) were significantly correlated with TT4RI (P = 0.034, 0.021, respectively). No significant associations were observed in males.</p><p><strong>Conclusions: </strong>OSA is associated with impaired central and peripheral thyroid hormone sensitivity in euthyroid females, but not in males.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"23"},"PeriodicalIF":5.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12870024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1186/s13293-025-00818-0
Alex Paterson, Su-Yi Loh, Shadi Kadijeh Gholami, Mark F Rogers, Dharmani Devi Murugan, Lam Sau-Kuen, Mohammad Rais Mustafa, Benjamin P Ott, Prusha Balaratnam, Andre S Mecawi, David Murphy, Charles C T Hindmarch
Background: Hypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals.
Methods: SHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10 mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis.
Results: in total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate.
Conclusions: T status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome.
{"title":"The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats.","authors":"Alex Paterson, Su-Yi Loh, Shadi Kadijeh Gholami, Mark F Rogers, Dharmani Devi Murugan, Lam Sau-Kuen, Mohammad Rais Mustafa, Benjamin P Ott, Prusha Balaratnam, Andre S Mecawi, David Murphy, Charles C T Hindmarch","doi":"10.1186/s13293-025-00818-0","DOIUrl":"10.1186/s13293-025-00818-0","url":null,"abstract":"<p><strong>Background: </strong>Hypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals.</p><p><strong>Methods: </strong>SHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10 mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis.</p><p><strong>Results: </strong>in total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate.</p><p><strong>Conclusions: </strong>T status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"22"},"PeriodicalIF":5.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12870226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.
Methods: Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.
Results: Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.
Conclusions: These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.
{"title":"Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice.","authors":"Keren Nitzan, Ziv Bentulila, Noa Bregman-Yemini, Niv Ayalon, Dekel David, Emanuela Break, Yossi Sarne, Ravid Doron","doi":"10.1186/s13293-025-00815-3","DOIUrl":"10.1186/s13293-025-00815-3","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.</p><p><strong>Methods: </strong>Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.</p><p><strong>Results: </strong>Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.</p><p><strong>Conclusions: </strong>These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"20"},"PeriodicalIF":5.1,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12866039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1186/s13293-025-00817-1
Ko-Hsiu Lu, Shiow-Ing Wang, Shun-Fa Yang
Background: To compare the effectiveness of romosozumab (ROMO) with parathyroid hormone (PTH) receptor agonists [teriparatide (TPTD)/abaloparatide (APTD)] in reducing fracture risk following osteoporosis treatment.
Methods: A TriNetX cohort study assessed fracture and mortality risks using Kaplan-Meier analysis with hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: After propensity score matching (n = 2,258 pairs), ROMO users had lower risks of osteoporotic fractures (HR: 0.711, 95% CI: 0.542-0.931) and hypercalcemia (HR = 0.707, 95% CI: 0.511-0.977) compared with PTH receptor agonists. Five subgroup analyses demonstrated a reduced fracture risk in the ROMO cohort among women (HR: 0.738), patients aged ≥ 65 years (HR: 0.652), individuals with a history of prior fractures (HR: 0.659), and those without chronic kidney disease (CKD) (HR: 0.731). Sensitivity analyses confirmed the robustness of the findings across different covariate adjustments, data sources, and extended follow-up, consistently showing a lower risk of hypercalcemia and nonsignificant trends toward reduced fracture risk in the ROMO cohort.
Conclusion: Compared with PTH analogs, ROMO offers stronger short-term protection against osteoporotic fractures and hypercalcemia, particularly in older women with prior fractures. Nonetheless, cardiovascular safety, calcium metabolism, and sequential therapy require careful consideration for individualized treatment.
{"title":"Real-world evidence indicates romosozumab use is associated with a greater reduction in osteoporotic fractures than PTH (1-34) analogs in women.","authors":"Ko-Hsiu Lu, Shiow-Ing Wang, Shun-Fa Yang","doi":"10.1186/s13293-025-00817-1","DOIUrl":"10.1186/s13293-025-00817-1","url":null,"abstract":"<p><strong>Background: </strong>To compare the effectiveness of romosozumab (ROMO) with parathyroid hormone (PTH) receptor agonists [teriparatide (TPTD)/abaloparatide (APTD)] in reducing fracture risk following osteoporosis treatment.</p><p><strong>Methods: </strong>A TriNetX cohort study assessed fracture and mortality risks using Kaplan-Meier analysis with hazard ratios (HRs) and 95% confidence intervals (CIs).</p><p><strong>Results: </strong>After propensity score matching (n = 2,258 pairs), ROMO users had lower risks of osteoporotic fractures (HR: 0.711, 95% CI: 0.542-0.931) and hypercalcemia (HR = 0.707, 95% CI: 0.511-0.977) compared with PTH receptor agonists. Five subgroup analyses demonstrated a reduced fracture risk in the ROMO cohort among women (HR: 0.738), patients aged ≥ 65 years (HR: 0.652), individuals with a history of prior fractures (HR: 0.659), and those without chronic kidney disease (CKD) (HR: 0.731). Sensitivity analyses confirmed the robustness of the findings across different covariate adjustments, data sources, and extended follow-up, consistently showing a lower risk of hypercalcemia and nonsignificant trends toward reduced fracture risk in the ROMO cohort.</p><p><strong>Conclusion: </strong>Compared with PTH analogs, ROMO offers stronger short-term protection against osteoporotic fractures and hypercalcemia, particularly in older women with prior fractures. Nonetheless, cardiovascular safety, calcium metabolism, and sequential therapy require careful consideration for individualized treatment.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":"21"},"PeriodicalIF":5.1,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12870266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1186/s13293-025-00803-7
Katherine Tombeau Cost, Eva Unternaehrer, Jens C Pruessner, Alex Abramovich, Kristin Cleverley, Peter Szatmari, Meng-Chuan Lai
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