Biology of Sex Differences最新文献

Computational phenotyping has emerged as a practical solution to the incomplete collection of data on gender in electronic health records (EHRs). This approach relies on algorithms to infer a patient's gender using the available data in their health record, such as diagnosis codes, medication histories, and information in clinical notes. Although intended to improve the visibility of trans and gender-expansive populations in EHR-based biomedical research, computational phenotyping raises significant methodological and ethical concerns related to the potential misuse of algorithm outputs. In this paper, we provide a narrative review of computational phenotyping of gender and examine its challenges through a critical lens. We also highlight existing recommendations for biomedical researchers and propose priorities for future work in this domain.

Darwin's [The Descent of Man (2nd Edn.) (1871)] theory of sexual selection has been expanded into a system of interlocking hypotheses to explain many features of sexual reproduction. It focusses on mating success and relies on processes featuring bad genes, selfishness, competition, conflict, coercion, ownership and deceit. Logical flaws and an absence of factual support challenge the sexual-selection system. An alternative explanatory system, social selection, focusses on offspring delivery and relies on processes featuring negotiation, teamwork and division of labor. The sexual-selection system and the social-selection system differ in their world views of nature.

Background: Biological sex and sociocultural gender may influence changes in health status critical to clinical decision-making, yet scientific evidence of their effects on clinically relevant outcomes remain uncertain. We aimed to systematically review research on sex and gender effects on clinical outcomes and to assess the consistency and significance of associations between sex, gender, and clinical outcomes.

Methods: We searched Medline, Embase, PsycInfo, CINAHL, and Web of Science from each database's inception to November 20, 2023, and included English language peer-reviewed research utilizing standardized measures of sex and gender attributes in adults to measure their association with clinically relevant outcomes. We performed a risk of bias assessment and certainty assessment using criteria set a priori. We created visualizations of results with links to study quality and sex and gender attributes, which facilitated certainty assessment. We reported results across sex and gender-related attributes and measures.

Results: Of the 12,964 unique records identified, 19 studies with a total of 643,093 participants (54% male) were included in data synthesis. Four studies measured attributes of sex (testosterone, sex-specific polygenic score), and 15 studies measured attributes of gender (gender identity, roles, and adherence to masculine norms). We observed great heterogeneity in the direction and significance of the associations, resulting in evidence of moderate certainty only for the association between testosterone level and depression, and erectile function. We regarded all other evidence as very low in certainty.

Conclusion: Research findings regarding the effects of sex and gender attributes on clinical outcomes is variable. However, results suggest that neither sex nor gender attributes should be ignored when investigating clinically relevant outcomes. To enhance certainty, future research should delve into sex and gender attributes concurrently, taking into account that clinical disorders are not evenly distributed across sexes and genders. This approach would provide needed evidence to drive precision medicine and person-centered care.

Prospero: CRD42023456917.

Funding: Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23-971123); Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074).

The liver is a central metabolic organ with pronounced sex-specific differences shaped by sex hormones, sex chromosome-linked gene expression, ageing, and circadian rhythm. These factors influence disease susceptibility, progression, and treatment response, with notable differences between females and males in the prevalence, severity, and clinical outcomes of metabolic dysfunction-associated steatotic liver disease. This condition represents a growing global health burden that can progress to hepatocellular carcinoma, the second leading cause of cancer-related death worldwide. Despite this impact, sex remains an underexplored variable in liver research, and the molecular mechanisms by which sex influences disease development remain poorly understood. In this review, we examine the key determinants of sex differences in liver pathogenesis. We highlight the protective role of estrogen signaling in female liver metabolism, the increased vulnerability to disease progression after menopause, and the contribution of circadian regulation to sex-specific outcomes. We further discuss how the lack of systematic inclusion of both sexes in preclinical and clinical studies limits the identification of biomarkers and the development of effective therapeutic interventions. Incorporating sex as a biological variable is therefore essential to improve mechanistic understanding, translational relevance, and the personalization of treatment approaches. Particular emphasis is placed on animal models that reflect sex-specific liver physiology and pathophysiology, as these provide valuable frameworks for studying disease progression and testing targeted interventions. In summary, recognizing and integrating sexual dimorphism in liver metabolism is crucial to advancing prevention, diagnosis, and treatment strategies. Addressing sex differences is critical for developing accurate diagnostic tools and personalized therapeutic approaches, ultimately improving outcomes for both women and men with liver disease.

Background: While it is clear that inflammation contributes to Parkinson's disease (PD) and prevalence is higher in males, sex remains an underexplored determinant of immune responses in PD.

Methods: Using the 3KL transgenic mouse model, which expresses three E to K α-synuclein mutations, we investigated how sex and age shape peripheral and central immunity and behavior in synucleinopathy. Male and female 3KL mice were aged to 8- and 14-months. At these ages animals underwent motor and cognitive assessment, followed by assessment of the peripheral immune response using flow cytometry and analysis of microglial transcriptional profiles by bulk RNA sequencing.

Results: Male 3KL mice exhibited earlier onset and greater severity of motor and cognitive impairments, which was linked to a pro-inflammatory peripheral immune profile marked by increased cytotoxic CD8⁺ T cells and IFNγ-producing CD4 Th1 cells. In contrast, female mice displayed delayed symptom onset, preserved cognition, along with early elevations in regulatory IL-10⁺ CD4 and γδ T cells. RNA sequencing of microglia revealed broad sex differences at 8 months. Males demonstrated early upregulation of microglia neurodegenerative signatures, MHC class I/II signaling, ceramide signaling, and pronounced lipid dysregulation, while females showed upregulation of microglial pathways related to protein, metabolic, and neuronal maintenance, including phagosome formation, docosahexaenoic acid signaling, and synaptogenesis pathways. Microglial transcriptional differences were nearly absent by 14 months, suggesting sex-specific trajectories converge during late-stage disease, which is concurrent with a decrease in estrogen in aged female mice.

Conclusions: Together, these findings reveal distinct immune signaling in male and female 3KL mice and identify coordinated changes in T cell and microglial responses that may contribute to sex differences in PD vulnerability and progression. This work underscores the importance of incorporating sex as a biological variable in neurodegeneration research and provides mechanistic insight into immune-mediated modulation of synucleinopathy.

Background: Polycystic ovary syndrome (PCOS) impairs endometrial receptivity, contributing to reproductive dysfunction. Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear.

Objective: We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS.

Methods: Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4's role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes.

Results: Phenotypic assessments revealed elevated endometrial Fe²⁺ accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates.

Conclusion: Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.

Debates about the nature of sex are prominent in scientific, scholarly and public discourses. Scientific as well as societal debates largely focus on whether sex is appropriately conceptualized as a binary, a spectrum, or some other form. These have taken on particular urgency because of highly contested, polarizing, and consequential developments in the global landscape in which the political weaponization of binary sex has escalated. Here we propose three frameworks useful for retaining focus on why sex might be conceptualized in a certain way to address the aims of a given project to help avoid pitting binary versus non-binary approaches against one another in a continued impasse. These three frameworks are (a) sex as a system of classification, (b) sex as a trait, and (c) sex as a dynamic system. We also provide a series of questions and considerations to guide a critical read of scholarship and scientific engagement of sex in ways that might help mitigate the isolating effects of disciplinary silos and advance cross-disciplinary dialogue and collaboration. Thus, rather than recapitulating discussions of how sex should be conceptualized or trying to establish a universally applicable definition of sex, these three frameworks and guiding questions can be drawn on to consider why certain projects might employ particular definitions and methods of operationalization of sex over others, and outline the merits and drawbacks of each. By refocusing our scholarly attention on what sex is empirically being employed to do and why, and providing these frameworks to think with, we hope to bring some essential bridging between those for and those against binary thinking about sex and foster a diversity of approaches that might more effectively build on one another rather than exist in opposition. We can then continue to try to nimbly engage what it is sex is being leveraged to do and why in order to ask how a given conceptualization will help us to learn about a given phenomenon.

Background: Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.

Methods: Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.

Results: In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.

Conclusions: The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.