Sex beyond the genitalia: The human brain mosaic

Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains (“female brain” or “male brain”). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only “male” or only “female” features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the “maleness-femaleness” continuum are rare. Rather, most brains are comprised of unique “mosaics” of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.The question of whether males and females form two distinct categories has attracted thinkers from ancient times to this day. Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved (for a historical overview, see refs. 1 and 2). Documented sex/gender^* differences in the brain are often taken as support of a sexually dimorphic view of human brains (“female brain” vs. “male brain”), and consequently, of a sexually dimorphic view of human behavior, cognition, personality, attitudes, and other gender characteristics (3). Joel (4, 5) has recently argued that the existence of sex/gender differences in the brain is not sufficient to conclude that human brains belong to two distinct categories. Rather, such a distinction requires the fulfillment of two conditions: one, the form of the elements that show sex/gender differences should be dimorphic, that is, with little overlap between the forms of the elements in males and females. Two, there should be a high degree of internal consistency in the form of the different elements of a single brain (e.g., all elements have the “male” form).Previous criticisms of the dichotomous view of human brain have focused on the fact that most sex/gender differences are nondimorphic population-level differences with extensive overlap of the distributions of females and males and have therefore claimed that human brains cannot be sorted into two distinct classes: “male brains” and “female brains” (6–8). However, if brains are internally consistent in the degree of “maleness-femaleness” of each of their elements, it will still be possible to align brains on a “male-brain–female-brain” continuum (4, 5). Such an alignment may be predicted by the classic view of sexual differentiation of the brain, according to which masculinization and defeminization of the brain are under the sole influence of testosterone (9). In contrast, more recent evidence that masculinization and feminization are independent processes and that sexual differentiation progresses independently in different brain tissues (10), predicts poor internal consistency (4, 5). Poor internal consistency is further predicted by evidence that the effects of sex may be different and even opposite under different environmental conditions and that these sex-by-environment interactions may be different for different brain features (4, 5). There are indeed examples of lack of internal consistency within a single brain in the animal literature (4, 5), yet it is not clear whether this is a common phenomenon that involves most features that show sex differences and is seen in most individuals. Here we assess the degree of internal consistency in the human brain using data obtained from MRI, a method that allows the simultaneous assessment of multiple brain features in many individuals.We used datasets obtained from several different imaging modalities and analyzed with different methods to ensure that our conclusion is not measure, analysis, or sample dependent. The number of subjects in these datasets ranged from 138 to 855. In each dataset, following an assessment of sex/gender differences in all regions, we focused on the regions showing the largest sex/gender differences (i.e., least overlap between females and males). Because also in these regions there was a considerable overlap between the distributions of females and males, which made a division into two distinct forms impossible, we tested whether individuals would be consistently at one end of the “femaleness-maleness” continuum across brain regions or show “substantial variability”, being at the one end of the “femaleness-maleness” continuum on some regions and at the other end on other regions. We found that regardless of sample, type of MRI, and method of analysis, substantial variability is much more prevalent than internal consistency.     

Sex differences in outcome following community-based cardiopulmonary arrest.

AIMS: To determine whether men and women suffering cardiopulmonary arrest differ in terms of survival and risk factors for survival. METHODS AND RESULTS: A prospective cohort study, using the Heartstart (Scotland) database, was undertaken on all 22 161 people suffering community-based cardiopulmonary arrest in Scotland between 1988 and 1997. The outcomes studied were death at the arrest scene, death before admission, death in hospital and death at any point up to discharge. Univariate analysis, using chi-square and Mann-Whitney U tests, was used to compare men and women in terms of patient characteristics, management and outcome. Multivariate logistic regression analysis was used to determine the association between sex and outcome after adjustment for case-mix. Sex differences in outcome varied over time. Women had a poorer risk profile than men. They were older (P<0.0001) and less likely to have shockable rhythms (P<0.0001). Despite this, they were more likely to survive to admission (P<0.0001). However, thereafter, women were more likely to die in hospital (P<0.01). There was no significant difference between the sexes in overall case-fatality rates to discharge. CONCLUSION: Women have a better early prognosis than men. However, this represents a postponement of death, rather than avoidance.     

作者单位：武汉大学人民医院心内二科,武汉,430060#$NL通讯作者：陈芳,S本科,主任护师,主要从事心电生理与心血管病护理的研究S

目的 调查湖北地区高血压患病率的性别差异,以期为高血压疾病防治策略提供循证科学依据。方法 2013年2月至2013年10月在湖北省咸宁咸安区、孝感应城县,采用分层多阶段随机抽样方法调查了4199名15岁以上当地居民。通过调查问卷及体格检查收集调查对象个人基本情况、身高、体重等所需要的资料。结果 男性及女性高血压患病率的最高峰均为75～,当地居民高血压患病率从25～起随着年龄的上升而增高,其中男性高血压患病率从25～起随着年龄的上升而增高,女性高血压患病率随着年龄的上升而增高;当地居民中,收缩压均值水平从25～起随着年龄的上升而增加,收缩压均值水平的高峰在75～,舒张压均值水平的高峰在45～。男性收缩压均值为124.54±15.25,舒张压均值为74.23±9.71;女性收缩压均值为121.29±17.48,舒张压均值为71.73±9.55。各年龄段间舒张压均值水平有统计学差异(P＜0.05)。就收缩压水平,男性及女性之间(F＝41.143,P<0.05),各年龄组之间(F＝129.021,P<0.05)均有统计学差异;就舒张压水平,男性及女性之间(F＝70.689,P<0.05),各年龄组之间(F＝16.641,P<0.05)均有统计学差异。结论 湖北地区男性及女性高血压患病率有统计学差异(P<0.05),从35～起到75～男性及女性高血压患病率有统计学差异(P<0.05)。     

Gender differences in giving blood: a review of the literature

Background

An overview of European blood donors shows that the distribution of men and women donors is similar in many countries, with Italy being an exception in that women account for only 30% of donors. Gender medicine is a key issue in this context, even though gender studies are very limited in the transfusion field, whether considered broadly or with specific regards to the selection, management and retention of donors. It, therefore, seemed important to compare the presence of women among blood donors in different European countries and examine the roles that gender is reported to play in the donation of blood in order to identify possible implications for communication with and management of the donor.

Methods

To determine the proportion of women among donors in European countries, data were collected from annual reports or documents available on the websites of national associations; furthermore, all papers related to giving blood published in the five main journals in the sector (Transfusion, Vox Sanguinis, Transfusion and Apheresis Science, Transfusion Medicine, Blood Transfusion) were considered; about 80 publications were selected and the gender variable was examined.

Results

The published studies showed that gender plays key roles in the motivation to give blood (women being more altruistic, men being more individualistic) and in adverse reactions, which was a particularly critical problem leading to fewer women become regular donors. A few aspects specific to the management of donors in Italy also emerged.

Discussion

Gender seems to play an important role in the aspects studied and does, therefore, merit further consideration in relation to strategies to recruit donors and the management of critical events during donation.     

Gender differences in the etiology of heart failure: A systematic review

Background

Heart failure (HF) is an increasing problem for the aging population, specifically among women. The etiology of HF influences both the selection and outcome of the treatment. There are variations between genders in morbidity and mortality in different studies, possibly reflecting etiology. The objective of this study was to examine the strength of evidence available for gender differences in the etiology of chronic heart failure.

Methods

Computer-assisted searches from 1980–2009 for gender differences in the etiology of heart failure were performed (Medline, EMBASE and PubMed). From 2347 abstracts reviewed based on inclusion criteria, 35 original articles were chosen for review. Data extraction was based on observational studies (prospective/retrospective cohort or cross sectional) with a mean follow up of 3 months. There was no interrater variability between the 2 reviewers on data-extraction.

Results

Ventricular systolic dysfunction being more associated with male sex, but female sex was more reported to be associated with preserved left ventricular function. Ischemic etiology and associated coronary heart disease were strongly correlated with male sex. The risk for HF was dramatically more elevated for women with systolic hypertension but the association for diabetes mellitus as the etiology of HF was somewhat equal between males and females.

Conclusions

One of the limitations in reaching conclusions about gender differences in cardiovascular disease is that many major clinical trials do not include a gender analysis nor they are powered to do so as women are under-represented in most of the HF studies. The need remains for a well designed prospective study of sufficient numbers of male and female patients with and without heart failure and analyzing etiology and risk factors based on the sex differences.     

Sex differences in obesity and the regulation of energy homeostasis

Obesity prevalence is generally higher in women than in men, and there is also a sex difference in body fat distribution. Sex differences in obesity can be explained in part by the influence of gonadal steroids on body composition and appetite; however, behavioural, socio-cultural and chromosomal factors may also play a role. This review, which evolved from the 2008 Stock Conference on sex differences in obesity, summarizes current research and recommendations related to hormonal and neuroendocrine influences on energy balance and fat distribution. A number of important gaps in the research are identified, including a need for more studies on chromosomal sex effects on energy balance, the role of socio-cultural (i.e. gender) factors in obesity and the potential deleterious effects of high-fat diets during pregnancy on the foetus. Furthermore, there is a paucity of clinical trials examining sex-specific approaches and outcomes of obesity treatment (lifestyle-based or pharmacological), and research is urgently needed to determine whether current weight loss programmes, largely developed and tested on women, are appropriate for men. Last, it is important that both animal and clinical research on obesity be designed and analysed in such a way that data can be separately examined in both men and women.     

Association of aerobic glycolysis with the structural connectome reveals a benefit–risk balancing mechanism in the human brain

Aerobic glycolysis (AG), that is, the nonoxidative metabolism of glucose, contributes significantly to anabolic pathways, rapid energy generation, task-induced activity, and neuroprotection; yet high AG is also associated with pathological hallmarks such as amyloid-β deposition. An important yet unresolved question is whether and how the metabolic benefits and risks of brain AG is structurally shaped by connectome wiring. Using positron emission tomography and magnetic resonance imaging techniques as well as computational models, we investigate the relationship between brain AG and the macroscopic connectome. Specifically, we propose a weighted regional distance-dependent model to estimate the total axonal projection length of a brain node. This model has been validated in a macaque connectome derived from tract-tracing data and shows a high correspondence between experimental and estimated axonal lengths. When applying this model to the human connectome, we find significant associations between the estimated total axonal projection length and AG across brain nodes, with higher levels primarily located in the default-mode and prefrontal regions. Moreover, brain AG significantly mediates the relationship between the structural and functional connectomes. Using a wiring optimization model, we find that the estimated total axonal projection length in these high-AG regions exhibits a high extent of wiring optimization. If these high-AG regions are randomly rewired, their total axonal length and vulnerability risk would substantially increase. Together, our results suggest that high-AG regions have expensive but still optimized wiring cost to fulfill metabolic requirements and simultaneously reduce vulnerability risk, thus revealing a benefit–risk balancing mechanism in the human brain.

The human brain is a highly complex system that requires energy metabolism as well as structural and functional connectivity to maintain normal function (1–5). Aerobic glycolysis (AG) refers to the nonoxidative metabolism of glucose despite the presence of adequate oxygen. In the resting adult human brain, the topography of AG exhibits a large regional variation, with significantly elevated levels in the medial and lateral parietal as well as the prefrontal cortices (6). Brain AG is particularly crucial for biosynthesis (7, 8), rapid production of ATP (9), task-induced activity (10), synaptic plasticity (e.g., synapse formation and growth) (11), and neuroprotection against oxidative stress (12). However, research suggests that higher levels of brain AG could be associated with higher risk of pathological hallmarks such as amyloid-β deposition (10, 13). Specifically, high-AG regions in young adults correspond to those regions that are later most vulnerable to amyloid-β deposition (14) and even subthreshold amyloid-β deposition (13). Thus, brain AG appears to have a dual role, playing both a positive role in maintaining the metabolic requirements of normal function, while also at the same time presenting a risk of vulnerability. In the present study, we approach brain AG from a mechanistic perspective, and investigate whether there is a basis in the underlying structural connectome that can account for the dual effects generated by AG in the brain.At the microscopic level, AG plays a vital role in the anabolic process (8). Specifically, AG produces acetyl CoA, a precursor for both fatty acid synthesis in myelination (15, 16) and amino acid synthesis in axonal elongation (17, 18). A metabolic transfer from the glycolytic oligodendroglia to the axons is necessary for long-term axonal integrity (9, 19–21). Moreover, AG alone is sufficient to support the maintenance of myelin in adulthood (9, 22, 23). Based on experimental observations of neuropathy (24) and animal models (25), researchers suggest that trophic support through glycolysis is wiring distance dependent, with longer axons associated with higher AG (26). These factors imply a tight association between AG and microscopic axonal structure. At the macroscopic level, high-AG regions tend to be highly centralized or part of the rich club in the structural network of the human brain (1, 27). This provides initial evidence for establishing a connection between regional AG levels and network topology. However, whether and how brain AG is structurally shaped by connectome wiring remains largely unknown.High-AG regions, which are primarily located in the default-mode and prefrontal cortices, largely overlap with brain hubs that are responsible for global communication (28–30). These regions also contain rich structural connections with other brain regions through axonal projections (31). From a supply–demand perspective, such regions require high glycolysis metabolism to support the large number of interregional axonal projections that are important for functional integration. However, high AG in the brain may carry a high risk of vulnerability. Specifically, studies of animal models in Alzheimer’s disease (AD) suggest an association between neuronal activity, lactate levels, and amyloid-β concentration in the brain (32, 33). During normal aging, the human brain undergoes topographic changes and a global loss of AG, with the greatest decline observed in areas corresponding to high-AG regions in young adult brains (34). As AG protects the brain from reactive oxygen species to prevent oxidative stress (12, 35, 36), the reduced levels of AG in the aging brain means a loss of neuroprotection, which may be one of factors that consequently leads to a higher risk of amyloid-β accumulation (37, 38). Meanwhile, as misfolded proteins are toxic to neurons, this may lead to a further loss of AG. Increasing evidence suggests that high-AG regions in healthy brains correspond to those regions that are highly vulnerable to amyloid-β deposition (14) and that may even constitute the main sites for early on-target subthreshold amyloid deposition (13). Therefore, from a risk control perspective, AG levels in these high-AG regions should not be further increased. This poses an interesting question in relation to the wiring mechanism in high-AG regions, specifically, whether these regions have a wiring-optimized design that avoids the need for even higher AG (i.e., which would otherwise be needed to support the longer axonal projections) and creating the potential for higher vulnerability risk.Based on these considerations, we hypothesized that high-AG regions in the human brain have large total axonal projection lengths to support functional integration between regions but that their wiring costs are optimized to avoid potentially high-risk situations created by excessive levels of AG. To address this hypothesis, we gathered two principal brain imaging datasets, the first set being positron emission tomography (PET) data (6), and the second set being high angular-resolution diffusion imaging (HARDI) and resting-state functional MRI (rsfMRI) data from the Human Connectome Project (HCP) (39). Here, PET data were applied to measure regional AG variations in the resting human brain, while HARDI and rsfMRI data were used respectively to acquire the brain’s structural and functional connectomes. Specifically, we proposed a computational model based on regional distance-dependent weights to estimate the structural wiring cost of a brain node by approximately capturing the total length of its axonal projections in the connectome. Such an approach was validated in a macaque structural connectome derived from tract-tracing data. Furthermore, we performed a mediation analysis to explore whether brain AG significantly mediates the relationship between the estimated regional total projection length and functional integration. To determine whether structural wiring costs in high-AG regions are optimized to reduce the risk of vulnerability, we compared the estimated regional total projection lengths in the structural connectome with those derived from either wiring-optimized or randomized network models. Studying the structural wiring rules underlying brain AG topography has important implications for understanding how the human brain allocates metabolic resources to achieve a benefit–risk balance.     

Narrowing gender differences in procedure use for acute myocardial infarction

OBJECTIVE: To examine age-specific gender differences and trends over time in the management of patients with acute myocardial infarction (AMI). DESIGN: Cross-sectional study of patients admitted with AMI from a community-wide perspective over a 10-year period (1990-1999). SETTING: All hospitals in the Worcester (Mass) metropolitan area (1990 census = 437000). PATIENTS/PARTICIPANTS: We identified 2037 women and 2645 men who were hospitalized in the Worcester metropolitan area with confirmed AMI during six 1-year periods between 1990 and 1999. Four age groups (<55, 55 to 64, 65 to 74 and >or=75 years) of men and women were studied. MEASUREMENTS AND MAIN RESULTS: Use of echocardiography, exercise treadmill testing (ETT), cardiac catheterization, percutaneous coronary interventions (PCI), and coronary artery bypass grafting (CABG) during the index hospitalization was examined in relation to age and gender. Overall, women were less likely to undergo ETT, cardiac catheterization, and CABG than were men, and these trends remained after controlling for potentially confounding factors. Between 1990 and 1999, there was a dramatic decrease in ETT, whereas the use of echocardiography remained unchanged. There were marked increases over time in the use of cardiac catheterization and PCI in women and men. Use of cardiac catheterization and PCI increased to a greater extent in women as compared to men. In patients who underwent cardiac catheterization, rates of coronary revascularization were similar between men and women. CONCLUSIONS: Our data suggest that women and men with AMI are treated differently with respect to use of diagnostic and revascularization procedures. However, gender differences in the use of these diagnostic and interventional approaches have narrowed over time.     

Sex differences in lipid profiles in relation to the progression of glucose abnormalities

Background: In the present study, we investigated the role of changes in blood lipids in the abolition of the lower cardiovascular risk associated with the female gender in individuals with type 2 diabetes mellitus (T2DM). Methods: An oral glucose tolerance test (OGTT) was performed in 1091 consecutive patients (478 men and 613 women) and patients were divided into groups as follows: (i) those with normal glucose tolerance (NGT; n = 589); (ii) those with pre‐diabetes (pre‐T2DM), who were further divided into those with impaired fasting glucose (IFG; n = 212), impaired glucose tolerance (IGT; n = 84), and both IFG and IGT (IFG/IGT; n = 102); and (iii) those with T2DM (n = 104). Total cholesterol, triglycerides, high‐density lipoprotein–cholesterol (HDL‐C), low‐density lipoprotein–cholesterol (LDL‐C), apolipoprotein (apo) A‐I, apoB, and the apoB:apoA‐I ratio were determined in each patient. Differences in lipids between the different groups were assessed using Student’s t‐test. Results: Significantly higher triglyceride levels and an apoB:apoA‐I ratio were found in NGT men (P < 0.0001), along with lower HDL‐C and apoA‐I (P < 0.0001). Men in the pre‐T2DM group maintained a higher apoB:apoA‐I ratio (P < 0.05) and lower HDL‐C (P < 0.0001) compared with women. In the T2DM group, only HDL‐C was lower in men compared with women (P < 0.05). Conclusions: The progression of glucose intolerance from NGT to pre‐T2DM and T2DM exhibits striking sex differences regarding the lipid profile. The data demonstrate a worsening of plasma lipid composition in women who become diabetic. This could explain, at least in part, the loss of the more favorable cardiovascular risk normally associated with NGT women.     

Sex differences in the origin of Purkinje ectopy-initiated idiopathic ventricular fibrillation

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Sex differences in ambulatory blood pressure monitoring

Purpose

Referral to ambulatory blood pressure monitoring may have bearing upon blood pressure control and prognosis. We describe sex-related differences in referral for ambulatory monitoring and their prognostic impact.

Methods

Between 1991 and 2005, 3957 patients were monitored in our ambulatory monitoring service, of whom 2114 (53%) were women. Demographic and clinical data were analyzed according to sex.

Results

Age (58 ± 15 vs 52 ± 17 years, respectively) and body mass index (27.5 ± 4.9 vs 26.9 ± 4.0 kg/m², respectively) were higher in women than men. Treatment for hypertension was more prevalent in women (62% vs 53%, respectively). Clinic systolic blood pressure (148 ± 24 vs 146 ± 20 mm Hg, respectively) and clinic pulse pressure (65 ± 22 vs 59 ± 18 mm Hg, respectively) were higher in women compared with men. In women, the white-coat effect was increased, compared with men; 5.2 ± 12.4% vs 1.5 ± 10.7% systolic, and 5.4 ± 11.2% vs 3.6 ± 10.3% diastolic. Consequently, women had lower ambulatory blood pressure than men. In women, 24-hour blood pressure was 136 ± 17/76 ± 10 vs 140 ± 15/81 ± 10 mm Hg in men, awake blood pressure 141 ± 17/80 ± 11 vs 144 ± 15/84 ± 10 mm Hg, and sleep blood pressure was 125 ± 19/67 ± 10 vs 127 ± 18/71 ± 11 mm Hg. Age-adjusted ambulatory blood pressure also was lower in women. Ambulatory heart rate was higher in women (P <.0001). Kaplan-Meier survival did not differ by sex (P = .66), despite older age and higher clinic blood pressure.

Conclusions

The results might imply that referral was driven by the physicians' overall patient risk perception. The greater magnitude of white-coat effect in women, and correspondingly lower ambulatory blood pressure, might in part account for similar mortality in the face of older age and higher clinic blood pressure.     

Sex differences in human biological aging

This study aims to clarify sex differences in human biological aging and to explore the gender gaps in health and longevity. Eighty-six men and 93 women who received a 2-day routine health checkup for 6-7 years beginning in 1992 at the Kyoto Red Cross Hospital were selected. Five candidate biomarkers of aging (forced expiratory volume in 1.0 second per square of height [FEV(1)/Ht(2)], systolic blood pressure [SBP], red blood cells [RBC], albumin [ALBU], and blood urea nitrogen [BUN]) were selected from 29 physiological variables. Individual biological ages (BAS) were estimated from these five biomarkers by a principal component model. From the investigation of the longitudinal changes of individual BAS, it was suggested that (i) beyond 65 years, the rate of aging showed a rapid increase, and (ii) women had relatively lower functional capabilities compared with men, but the rate of aging was slower than that of men, suggesting that these differences might present both disadvantages and advantages for women with regard to health and longevity.     

Sex differences in brain activation elicited by humor

With recent investigation beginning to reveal the cortical and subcortical neuroanatomical correlates of humor appreciation, the present event-related functional MRI (fMRI) study was designed to elucidate sex-specific recruitment of these humor related networks. Twenty healthy subjects (10 females) underwent fMRI scanning while subjectively rating 70 verbal and nonverbal achromatic cartoons as funny or unfunny. Data were analyzed by comparing blood oxygenation-level-dependent signal activation during funny and unfunny stimuli. Males and females share an extensive humor-response strategy as indicated by recruitment of similar brain regions: both activate the temporal-occipital junction and temporal pole, structures implicated in semantic knowledge and juxtaposition, and the inferior frontal gyrus, likely to be involved in language processing. Females, however, activate the left prefrontal cortex more than males, suggesting a greater degree of executive processing and language-based decoding. Females also exhibit greater activation of mesolimbic regions, including the nucleus accumbens, implying greater reward network response and possibly less reward expectation. These results indicate sex-specific differences in neural response to humor with implications for sex-based disparities in the integration of cognition and emotion.