Biology of Sex Differences最新文献

Background: Sex and gender both affect health outcomes, often in complex ways that intertwine biological and social influences. While researchers have criticized the conflation of sex and gender in quantitative studies, it remains a challenge to analytically disentangle them. We investigated an approach to conceptualize sex and gender as interrelated constructs embedded within a specific social context and estimate their direct effects on health outcomes simultaneously.

Methods: To analyze migraine and stroke incidence from 2011 until 2022, we used longitudinal data from the representative German Socio-Economic Panel (SOEP) within a causal framework. We applied a directed acyclic graph (DAG) to formalize hypothesized effects of sex and gender. Gender was modeled as an unobserved latent variable, influenced by sex assigned at birth and indicated by a set of gender-related variables. We codified the causal model as a structural equation model (SEM), enabling the joint estimation of the latent gender construct and the direct effects of both sex and gender on the health outcomes. We tested prior hypotheses in the SEM and explored additional relationships using causal discovery techniques.

Results: Migraine incidence was 3.1 times higher among participants of female sex (6.2% vs. 2.0%). Sex had the strongest effect on reporting a new migraine diagnosis (β = 0.044, 95% CI [0.033, 0.056], p < .001), while gender showed no direct effect. Stroke incidence was lower among female respondents (1.2% vs. 1.7%), with sex showing a statistically significant negative effect, indicating that slightly fewer female persons reported a new stroke diagnosis (β = -0.010, 95% CI [-0.017, -0.004], p < .01). In contrast, gender showed a small, but significant positive effect (β = 0.006, 95% CI [0.002, 0.009], p < .01), suggesting that gender-related characteristics that were more frequently reported by female individuals had an effect on stroke incidence.

Conclusions: Both sex and gender differentially affected stroke, whereas only sex showed a direct effect on migraine. We demonstrated that biological and social dimensions of sex and gender can be systematically addressed within the same model including gender as an unobserved latent variable, while remaining attentive to contextual complexity.

Background: Comprehending sex differences in stress vulnerability and the associated neurocircuitry has been elusive until the development of a method for investigating social defeat in female mice.

Methods: The Stress Alternatives Model (SAM) uses conditioning-induced agonistic behavior from novel male aggressors to separate distinct phenotypes characterized by stress-resilient active avoidance (Escape) or vulnerability (no Escape = Stay).

Results: Unlike males, females predominantly display Escape behavior, which is reversible (to Stay) by adding more social stress to behavioral environments. Despite this, females exhibit both stress-resilient and vulnerable phenotypic segregation. Stress-vulnerable females exhibit double conditioning-induced corticosterone secretion, more contextual fear conditioning, and reduced social preference. Systemic and intra-BLA injections of Orx₂R or α₂ antagonists resulted in slower escape (Escape^S), increased social avoidance, as well as increased cued and contextual freezing in stress-vulnerable females. Neurons in BLA express Orx₂R mRNA (Hcrtr2) predominantly in cholecystokinin-positive GABA neurons. In slower escape (Escape^S) females expression of Hcrtr2 and Adra2a in BLA is elevated.

Conclusions: Female and male mice exposed to social stress exhibit distinct behavioral adaptations, but similarly, separate into resilient and susceptible subpopulations. Inhibiting Orx₂R promotes stress-vulnerable behavior in females, and modifies transcription in BLA microcircuits, suggesting a role for Orx₂R defining stress behavior.

Background: The age-specific magnitude of the impact of hormones on aging and the role of hormone replacement therapy (HRT) remain unclear.

Methods: We used data from UK Biobank participants for our analysis. Linear and logistic regression models were employed to investigate the associations and its differences between estradiol/testosterone and biological age acceleration (BAA) across different age group. Then, females were divided into HRT and non-HRT groups, and restricted cubic splines were used to evaluate HRT initiation age and duration.

Results: A total of 54,912 participants (71.99% females, 28.01% males) were enrolled, with 39,303 females assessed for the impact of HRT on aging. Estradiol decline in females was linked to a 0.18-0.29-year BAA increase, while testosterone decline in males was linked to a 0.07-0.71-year BAA increase. It showed estradiol protected against aging in females (most prominent at 41-55 years) while elevated testosterone accelerated aging. In males, testosterone was protective (most significant at 56-70 years) and estradiol had no notable effect. Quartile and age-stratified analyses confirmed these findings. In contrast, the decrease of estradiol was associated with biological age younger. Hormone replacement therapy (HRT) in females resulted in sustained BAA reduction (-4.5 to -6.0, 41-70 years) superior to non-HRT (-4.0 to -5.5). HRT initiated at 56-60 years showed optimal efficacy, with longer duration associated with more pronounced aging deceleration.

Conclusions: The impact of per standard deviation (SD) decrease in sex hormone levels on aging (BAA) varies by age, with significant effects observed in females aged 50-55 years and males aged 65-70 years. These findings may facilitate the optimization of HRT timing to maximize anti-aging benefits and enable personalized treatment strategies.

Background: Social isolation is a chronic psychological stressor with high translational relevance to depression in humans, particularly in the aftermath of the COVID-19 pandemic. However, few preclinical studies have evaluated its sex-dependent effects. Some studies have shown that after four weeks of social isolation, only males exhibit depressive-like behavior, without a comprehensive view of the underlying immune and neuroimmune alterations.

Methods: Here, we examined the impact of prolonged social isolation on depressive- and anxiety-like behaviors of adult male and female mice, using the forced swim, splash, open field, and light/dark box tests. We also analyzed peripheral immune profiles through flow cytometry, ELISA and qRT-PCR, and neuroimmune responses through qRT-PCR and immunofluorescence for astrocytes and microglia.

Results: After seven weeks of social isolation, both males and females exhibited depressive-like behavior and inflammatory signs such as elevated neutrophils in circulation, decreased IL-10 expression in the spleen, higher expression of IDO in the hippocampus, and higher microglia number. However, sex-related differences were also detected. Isolated males show lower body weight, with no changes in corticosterone levels, while isolated females exhibit increased corticosterone levels, higher IL-1β expression in the hippocampus, and higher microglia total area.

Conclusions: After seven weeks of social isolation, both sexes exhibit depressive-like behavior, with sex-related differences in body weight, corticosterone levels, and cellular and molecular signs of neuroinflammation. These findings highlight the importance of temporality and sex as key variables in the behavioral and physiological responses to chronic stress. Given the increased prevalence of depression in women, these results provide new insights into sex-specific susceptibility to chronic stress and may inform the development of tailored diagnostic and therapeutic strategies.

Background: A priority in aging and dementia research is to integrate sex (biological attribute) and gender (sociocultural/behavioural characteristics) in theories, designs, analyses, and intervention protocols. We recently reported a data-mining procedure for operationalizing empirically-derived composite gender variables in archival databases. The present study extends the prior cross-sectional approach by examining sex and gender as separate and interactive predictors of longitudinal data-driven memory trajectory classes.

Methods: Participants (N = 746) contributed baseline data for binary sex (female/male), education (years), and empirically-derived composite variables representing complementary gender facets. These facets included Manual Tasks and Physical Activities; Social and Household Management; Leisure, Socializing, and Travel; Cognitive Activity and Brain Games; Health Perceptions and Practices; and Subjective Memory Beliefs. We integrated these into a longitudinal episodic memory trajectory distribution spanning 42 years (53-95) of aging. Data-driven latent class growth analysis (LCGA) on the trajectory distribution identified discriminable classes. Using the R3STEP approach, we separately tested sex, gender facets, and education as predictors of membership in the higher (healthier) trajectory classes relative to the lowest (benchmark) class. We then included interaction terms to test for sex moderation of gender effects. Finally, we identified all genotyped participants and tested whether sex and gender effects were moderated by Apolipoprotein E (APOE).

Results: LCGA revealed three memory classes: High-Stable (highest level/relatively stable), Moderate/Normal-Declining (average level/moderate decline), and Low-Declining (lowest level/steepest decline). Several variables separately predicted High-Stable membership. For sex, females were more likely than males to belong to this class. For gender, (a) higher scores for Social and Household Management, Cognitive Activity and Brain Games, and Subjective Memory Beliefs predicted High-Stable membership; and (b) higher scores for Manual Tasks and Physical Activities and Health Perceptions and Practices decreased the likelihood of High-Stable membership (relative to Low-Declining). Moderate/Normal-Declining membership was predicted by Social and Household Management (higher). For education, more years predicted High-Stable membership. Moderation analyses indicated that gender effects were consistent across both sexes and APOE carrier status.

Conclusions: Data-driven analyses show that biological sex and measurable facets of gender differentially contribute to memory trajectory patterns over a 42-year span of cognitively unimpaired aging.

Contemporary understanding of key neural processes has advanced the study of the dynamic, iterative influences between the brain and external events, contributing to a growing evidence base concerning the entanglement between human brain structure and function and socio-cultural contextual factors, with consequent behavioural implications. This is particularly relevant to any understanding of differences in apparently sex-linked human behavioural phenotypes and the role of external factors in producing such differences. Relevant insights are provided not only by the relatively well-established concept of experience-based neuroplasticity, but also by research into the brain-changing effects of social context, which can include gendered attitudes and expectations. The developing study of the socially embedded brain offers a powerful organising framework to inform both methodological and theoretical approaches to an understanding of the brain-based mechanisms of biology/society interactions. Additionally, the emerging application of models of predictive coding processes in the brain to human social behaviour potentially offers wide-ranging insights into the role of rule-based, socio-culturally determined, lived experiences in shaping brain development and function and tracking. This paper aims to demonstrate how this framework could be harnessed in neuroscience research into the dynamic entanglement between sex-related brain processes and social contextual influences such as gender.

Background: The significance of sex differences in auditory function and vulnerability to hearing disorders has gained increasing attention. However, the underlying biological mechanisms remain unclear. Estrogen and other female hormones are known to regulate gene expression in various organs and tissues. However, their role in regulating gene expression in the cochlea remains to be determined. The current study investigated how female hormonal status, through natural fluctuations of the estrous cycle and hormonal deprivation via ovariectomy, modulates cochlear gene expression in mice.

Methods: The cochlear transcriptome was examined under two experimental conditions that alter female hormones level: the normal estrous cycle and surgical removal of the ovaries (ovariectomy), with or without subsequent estradiol treatment. RNA sequencing was used to profile cochlear transcriptomes, followed by bioinformatic analyses to identify differentially expressed genes and their associated biological processes.

Results: Our study identified a set of cochlear genes whose expression varies between the proestrus and diestrus stages of the estrous cycle. Most of these cochlear genes are autosomal protein-coding genes. There were more diestrus-biased genes compared to proestrus-biased genes. Many of these estrous cycle-regulated genes have been previously reported as hormone-responsive and encompass a range of functional categories, particularly those involved in regulating cellular function. The differentially expressed genes are primarily associated with immune-related functions. Notably, immune-related genes showed higher expression during diestrus. Our study also showed that ovariectomy altered cochlear gene expression, though it influenced only a limited number of genes. Ovariectomy-modulated genes were primarily associated with inflammatory responses and autophagy. Furthermore, several ovariectomy-induced changes were reversed by estradiol treatment, highlighting the regulatory role of this hormone in cochlear gene expression.

Conclusions: Both natural hormonal fluctuations across the proestrus and diestrus stages of the estrous cycle, as well as experimental hormone manipulation through ovariectomy and estradiol treatment, can modulate cochlear gene expression. These findings suggest that hormone-driven transcriptional changes may contribute to sex differences in auditory physiology and disease vulnerability.

Background: Disorders of Sex Development (DSD) refer to a group of congenital conditions where chromosomal, gonadal, or anatomical sex development is atypical. Cardiovascular diseases (CVD) are a leading cause of illness and death worldwide, often resulting in serious conditions like heart attacks, strokes, and heart failure. Recent research suggests that shared mechanisms may link DSD and CVD. This study aims to investigate the shared genetic mechanisms between DSD and CVD, which could uncover common biological pathways involved in their development.

Methods: We performed a comprehensive analysis using a dataset of 169 genes associated with 46XY DSD and corresponding genes linked to CVD, gathered from published research. The overlapping genes between them were identified and grouped into four biological processes: transcription factors, signaling pathways, hormonal regulation, and developmental regulation.

Results: In this review, we explored the potential link between recognized 46XY DSD genes and CVD. We found 25 genes that are shared between the 46 XY DSD and CVD, suggesting a genetic connection between the two conditions. These shared genes fall into categories such as transcription factors, signaling pathways, hormonal regulation, and developmental regulation. This gives us valuable insights into how these genetic factors might affect cardiovascular health in people with DSD. Each gene and its role in 46XY DSD and CVD will be discussed separately. We will also address challenges and provide suggestions for a better understanding of the genetics involved. Additionally, the review will outline future research directions crucial for advancing our understanding of the connection between 46XY DSD and CVD, with the goal of improving health outcomes for affected individuals.

Conclusions: Our findings suggest a genetic link between 46 XY DSD and CVD, indicating that shared molecular mechanisms may play a role in the development of both conditions. These insights into the connections could have important implications for personalized medicine, potentially allowing for treatments that target both 46 XY DSD and CVD.

Background: Females undergo hormonal fluctuations throughout every menstrual cycle and numerously report corresponding symptoms of negative mood or decreased motivation, indicating an increased risk for affective disorders associated with altered motivational behaviour. Understanding whether sex hormones modulate sex/gender-specific behavioural variability in motivation could inform personalised interventions.

Methods: To assess whether steroid hormone fluctuations and menstrual cycle phase modulate sex/gender-specific motivation, we examined 48 naturally cycling cisgender females and 46 cisgender males, aged 18-34, who performed a physical effort task while fasted (part 1, T0) and across four weeks (part 2, T1-T4). We obtained objective (invigoration and effort maintenance) and subjective (wanting and exertion) measures of motivation in response to food and monetary rewards. Menstrual cycle phases were determined based on cycle-day counting methods alongside plasma levels of estradiol, progesterone, and testosterone. We tested whether females show higher effort maintenance, males exhibit greater reward sensitivity, and explored whether motivational behaviour differs by sex/gender, cycle phase and hormonal variation.

Results: Cross-sectionally, we replicated sex/gender specific reward sensitivity and valuation: Females showed more sustained effort, especially for small rewards, while males displayed more opportunistic approaches seeking monetary rewards. Longitudinally, motivation decreased during periovulatory and luteal phases, whereas levels of endogenous hormones explained little variance in instrumental effort beyond task incentives and sex/gender associations.

Conclusions: Motivational behaviour in effort-based decision-making is more related to dynamic sex/gender-related factors and menstrual cycle phases overall than to short-term steroid hormone fluctuations. Our findings emphasise the importance of integrating biological, psychosocial, and physiological factors when investigating motivation. Our research has potential implications for personalised interventions and treatment of motivational deficits.