Sex Differences In Research Research Articles

Sex Differences Across the Lifespan: A Focus on Cardiometabolism.

Women's health and sex differences research remain understudied. In 2022, to address the topic of sex differences, the Ludeman Family Center for Women's Health Research (LFCWHR) at the University of Colorado (LudemanCenter.org) held its third National Conference, "Sex Differences Across the Lifespan: A Focus on Metabolism." The research presentations and discussions from the 2022 conference addressed cardiometabolic sex differences across the lifespan and included sessions focusing on scientific methods with which to study sex differences, effects of estrogen on metabolism, and sex differences in cardiovascular disease-implications for women and policy among others. Over 100 participants, including basic scientists, clinical scientists, policymakers, advocacy group leaders, and federal agency leadership participated. The meeting proceedings reveal that although exciting advances in the area of sex differences have taken place, significant questions and gaps remain about women's health and sex differences in critical areas of health. Identifying these gaps and the subsequent research that will result may lead to important breakthroughs.

Statistical indices of masculinity-femininity: A theoretical and practical framework

Statistical indices of masculinity-femininity (M-F) summarize multivariate profiles of sex-related traits as positions on a single continuum of individual differences, from masculine to feminine. This approach goes back to the early days of sex differences research; however, a systematic discussion of alternative M-F indices (including their meaning, their mutual relations, and their psychometric properties) has been lacking. In this paper I present an integrative theoretical framework for the statistical assessment of masculinity-femininity, and provide practical guidance to researchers who wish to apply these methods to their data. I describe four basic types of M-F indices: sex-directionality, sex-typicality, sex-probability, and sex-centrality. I examine their similarities and differences in detail, and consider alternative ways of computing them. Next, I discuss the impact of measurement error on the validity of these indices, and outline some potential remedies. Finally, I illustrate the concepts presented in the paper with a selection of real-world datasets on body morphology, brain morphology, and personality. An R function is available to easily calculate multiple M-F indices from empirical data (with or without correction for measurement error) and draw summary plots of their individual and joint distributions.

The harm hypothesis: How perceived harm to women shapes reactions to research on sex differences.

Past research suggests that reactions to research on sex differences are often less positive when the findings put men in a better light than women, especially when the lead researcher is a man. The factors underlying this effect, however, are not yet fully understood. The present study aimed to provide the first experimental test of the hypothesis that the key variable is perceived harm to women. Participants (214 men and 219 women) evaluated a bogus popular-science article reporting fictional research finding either a female- or a male-favouring sex difference in intelligence, attributed to either a female or a male lead researcher. To examine the effects of perceived harm, the introduction to the task highlighted either the potential benefits or potential drawbacks of sex-differences research in general. Consistent with past research, participants reacted less positively to the male-favouring difference, especially for male-led research. Consistent with the harm hypothesis, the effect was stronger after highlighting the potential drawbacks of sex-differences research than after highlighting the potential benefits. Our findings suggest that perceptions of harm to women underpin the aversion to male-favouring findings.

Novel Collaborations Across Training Programs to Support Mentoring in Sex Differences Research.

There is a critical need to develop a capable and well-trained workforce dedicated to the systematic study of sex differences and examination of sex as a biological variable. Through the support of the Office of Research on Women's Health and partner National Institute of Health centers, the Specialized Centers of Research Excellence (SCORE) on Sex Differences Career Enhancement Cores (CECs) were established to help address this need. We describe the integration of the Medical University of South Carolina SCORE CEC with other National Institutes of Health (NIH)-funded and institutional training programs to promote training synergies, share resources, and enhance mentorship opportunities. Benefits of developing an intrainstitutional training platform have included facilitating cross-disciplinary interactions, encouragement of peer mentorship, and reduced burden on training program leadership.

Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic Aging Tenacity ("You are never too old to become younger!") Specialized Center of Research Excellence on Sex Differences Career Enhancement Core: Building the Future.

The objective of the National Institutes of Health Office of Research in Women's Health (NIH/ORWH) Specialized Center of Research and Career Enhancement (SCORE) program is to expedite the development and application of new knowledge that affect women, to learn more about the etiology of these diseases, and to foster improved approaches to treatment and/or prevention. Each SCORE has a Career Enhancement Core (CEC) that serves to meet the career enhancement needs of translational science in the study of sex differences. The Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic aging Tenacity (MAE-WEST) ("You are never too old to become younger!") Specialized Center of Research Excellence (SCORE) on Sex Differences will study pro- and anti-inflammatory responses and small vessel aging traits. As part of our SCORE CEC, we have advanced several initiatives to embed consideration of sex as a biological variable (SABV) into the infrastructure of our two CEC institutions. Unlike other professions, ongoing physician education through continuing medical education (CME) activities is required and embedded in the practice of medicine. The MAE-WEST SCORE in collaboration with the CSMC Clinical Scholars Program, the Center for Research in Women's Health and Sex-differences and the CSMC CME Office requires SABV and as Diversity, Equity, and Inclusion components in all CSMC CME programs. Clinical practice is also increasingly guided by evidence-based guidelines, with Class I recommendations resulting from clinical trials rather than expert consensus. It is essential that women be included in clinical trials proportionate to the prevalence and burden of disease. The MAE-WEST SCORE has developed our own unique CEC for providing novel educational, networking, funding opportunities, and translation to practice support. The developed best practices have found novel ways to enhance studies of women's health and SABV. We welcome visitors on-site and virtual to share with the broader academic and practicing community.

Addressing persistent evidence gaps in cardiovascular sex differences research - the potential of clinical care data.

Women have historically been underrepresented in cardiovascular clinical trials, resulting in a lack of sex-specific data. This is especially problematic in two situations, namely those where diseases manifest differently in women and men and those where biological differences between the sexes might affect the efficacy and/or safety of medication. There is therefore a pressing need for datasets with proper representation of women to address questions related to these situations. Clinical care data could fit this bill nicely because of their unique broad scope across both patient groups and clinical measures. This perspective piece presents the potential of clinical care data in sex differences research and discusses current challenges clinical care data-based research faces. It also suggests strategies to reduce the effect of these limitations, and explores whether clinical care data alone will be sufficient to close evidence gaps or whether a more comprehensive approach is needed.

Learning processes in relapse to alcohol use: lessons from animal models.

Alcohol use is reliably preceded by discrete and contextual stimuli which, through diverse learning processes, acquire the capacity to promote alcohol use and relapse to alcohol use. We review contemporary extinction, renewal, reinstatement, occasion setting, and sex differences research within a conditioning framework of relapse to alcohol use to inform the development of behavioural and pharmacological therapies. Diverse learning processes and corresponding neurobiological substrates contribute to relapse to alcohol use. Results from animal models indicate that cortical, thalamic, accumbal, hypothalamic, mesolimbic, glutamatergic, opioidergic, and dopaminergic circuitries contribute to alcohol relapse through separable learning processes. Behavioural therapies could be improved by increasing the endurance and generalizability of extinction learning and should incorporate whether discrete cues and contexts influence behaviour through direct excitatory conditioning or occasion setting mechanisms. The types of learning processes that most effectively influence responding for alcohol differ in female and male rats. Sophisticated conditioning experiments suggest that diverse learning processes are mediated by distinct neural circuits andcontribute to relapse to alcohol use. These experiments also suggest that gender-specific behavioural and pharmacological interventions are a way towards efficacious therapies to prevent relapse to alcohol use.

264 Challenges of Sex Differences Research in Neuroscience: The role of central estradiol in heroin extinction memory retention in male and female rodents

OBJECTIVES/GOALS: Misprescription of opioids has led to an epidemic of opioid use disorder (OUD). Females, among other differences, have increased susceptibility to the addictive properties of opioids. Yet, the exclusion of female subjects from many foundational studies on reward processing had hindered our ability to fully understand these disparities. METHODS/STUDY POPULATION: Estradiol (E2), a neuronal sex steroid, may play a role in sex differences in OUD. In this study, we used fadrozole, an aromatase inhibitor, to characterize the role of centrally produced E2 in heroin cue extinction memory retention (EMR, “remembering to forget”). Male and female rats self-administered heroin in a long-access paradigm (6hr/day) for 8 days, where a light/tone cue was co-presented with each infusion of heroin. This was followed by 1 day of cued extinction (6hr; light/tone but no heroin). Just prior to this session, fadrozole was infused into the basolateral amygdala (BLA) through implanted cannulas. The next day, subjects were given a cued EMR test (1hr; light/tone but no heroin) following another infusion of fadrozole. RESULTS/ANTICIPATED RESULTS: Females took more heroin than males (mg/kg) despite having similar active nose poke responding during acquisition. Regardless of aromatase inhibition, females had higher active nose pokes during the first hour of cued extinction relative to males. Both males and females treated with fadrozole in the BLA prior to cued extinction had impaired EMR on test, evidenced by increased active nose pokes and lower extinction indices relative to vehicle controls. Upon examination of the brains, we expect that aromatase inhibition will have impaired neuronal plasticity, as evidenced by decreases in numerous measures of plasticity. Furthermore, we expect to find sex differential expression of estrogen receptor (ER) subtypes throughout the BLA, suggesting a convergent sex effect of E2 on heroin EMR. DISCUSSION/SIGNIFICANCE: This study is the first to examine a behavioral role for central E2 in the BLA. Future studies will examine specific roles for ER subtypes on this behavior and synaptic plasticity. A better understanding of sex specific E2 signaling will promote further research on sex differences and allowing us to better address disparities in disorders like OUD.

Sex differences in online assertive self-presentation strategies

This study explored differential relationships between assertive self-presentational strategies and social media behaviour between females and males, and these are the same for selfie and non-selfie images. Four hundred and thirty six participants completed the study (253 females, 183 males; mean age = 21.24 years, range 18–30). They completed the Self-Presentation Tactics Scale (Assertive), and a week later the number of selfie-postings, selfie-edits, and total number of photo postings, on each participant's social media sites were counted. Females posted and edited more selfies than males, with no difference in non-selfie image posting. Males showed greater assertive self-presentational strategies of entitlement, enhancement, blasting, and ingratiating, but not intimidation. There was a complex relationship between sex and social media behaviour. The primary presentational strategy associated with selfie posting for females was intimidation, with a larger range of strategies associated with selfie posting for males. Both sexes showed associations between aggressive self-presentational strategies and non-selfie posting, but these associations were stronger for the males, in that those males with high levels of such strategies posted more non-selfies. These results are not easily characterised by either evolutionary or social role theories, but suggest online behaviour offers novel opportunities for sex difference research.

Sex Differences Across the Lifespan: A Focus on Cardiometabolism.

Women's health and sex differences research remain understudied. In 2016, to address the topic of sex differences, the Center for Women' s Health Research (CWHR) at the University of Colorado (cwhr@ucdenver.edu) held its inaugural National Conference, "Sex Differences Across the Lifespan: A Focus on Metabolism" and published a report summarizing the presentations. Two years later, in 2018, CWHR organized the 2nd National Conference. The research presentations and discussions from the 2018 conference also addressed sex differences across the lifespan with a focus on cardiometabolism and expanded the focus by including circadian physiology and effects of sleep on cardiometabolic health. Over 100 participants, including basic scientists, clinicians, policymakers, advocacy group leaders, and federal agency leadership participated. The meeting proceedings reveal that although exciting advances in the area of sex differences have taken place, significant questions and gaps remain about women's health and sex differences in critical areas of health. Identifying these gaps and the subsequent research that will result may lead to important breakthroughs.

The effect of sex on multiple sclerosis risk and disease progression

Sex differences in the incidence or severity of disease characterize many autoimmune and neurodegenerative diseases. Multiple sclerosis is a complex disease with both autoimmune and neurodegenerative aspects and is characterized by sex differences in susceptibility and progression. Research in the study sex differences is a way to capitalize on a known clinical observation, mechanistically disentangle it at the laboratory bench, then translate basic research findings back to the clinic as a novel treatment trial tailored to optimally benefit each sex. This “Bedside to Bench to Bedside” approach based on sex differences in MS will be reviewed here, first for disease susceptibility then for disability progression.

Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise.

Adolescence is a highly dynamic period of development, which includes the final organizational phases of neural maturation within the prefrontal cortex (PFC). The organizational events of neural pruning and myelination occur in a sex-specific manner, potentially giving rise to the disparities in mood disorders in adulthood. Because of the extended developmental time period of the PFC, environmental insults, including psychosocial stressors, may play a major role in steering the maturation of this region. In this review, the literature surrounding the sex specific alterations that occur in the PFC in rodent models following adolescent stress will be discussed. This will be complimented by a brief review on the state of human research in PFC sex differences in the development of white matter and cytoarchitecture across the lifespan. Taken together, the impact of developmental psychosocial stress on the circuitry of the PFC and resulting adult phenotypes will be summarized with a focus on the importance of considering sex differences in order to build a better understanding of developmental influences on adult disorders.

Psychometric Properties of the Multifaceted Gender-Related Attributes Survey (GERAS).

Since the 1920s, psychologists have sought to assess the sex- and gender-related attributes of men and women, including primarily aspects of personality and focusing on positive characteristics. In this paper, we introduce a new questionnaire for assessing gender-related attributes with a broader approach than provided by previous ones. Therefore, the questionnaire includes (a) not only personality traits but also cognitions and interests and (b) not only positive but also negative and neutral characteristics. Two independent datasets were acquired (Study 1: N = 1,466; Study 2: N = 471) for development and psychometric analyses. Factor analysis confirmed a hierarchical structure with two separate dimensions of masculinity and femininity overarching the multiple first-order domains of personality, cognition, and interests. Analyses of reliability and convergence with other gender identity and personality scales revealed sufficient values. The new instrument discriminated between the biological sexes and was related to the gender quotas in participants' occupations and social environments, thus providing evidence for criterion-related validity. Therefore, we propose the Gender-Related Attributes Survey (GERAS) as a useful tool for objectively assessing gender-related attributes across multiple facets in gender and sex-difference research.

Sex differences in education: exploring children’s gender identity

Gender stereotypes associate mathematics and sciences with boys, whereas reading and writing are typically associated with girls. This study investigated sex differences in primary school children’s motivation (confidence and value) across four academic subjects (maths, science, reading and writing) and examined how their identification with stereotypical masculine and feminine traits related to their motivation in these subjects. Five hundred and thirty-two children (aged 9–11, 52% boys), from five UK schools participated. Sex differences in reading and writing motivation were wider than sex differences found in maths and science motivation. Interestingly, the extent to which children identified with feminine traits was a stronger predictor of their reading and writing motivation than their sex. Gender identity provides an innovative approach to the study of sex differences; it challenges the dichotomy inherent within sex differences research and can lead to a more critical and nuanced understanding of sex differences in education.

Sex differences in behavior and neuropharmacology of zebrafish.

Sex is an important variable in biomedical research. The zebrafish (Danio rerio) is increasingly utilized as a powerful new model organism in translational neuroscience and pharmacology. Mounting evidence indicates important sex differences in zebrafish behavioral and neuropharmacological responses. Here, we discuss the role of sex in zebrafish central nervous system (CNS) models, their molecular mechanisms, recent findings and the existing challenges in this field. We also emphasize the growing utility of zebrafish models in translational neuropharmacological research of sex differences, fostering future CNS drug discovery and the search for novel sex-specific therapies. Finally, we highlight the interplay between sex and environment in zebrafish models of sex-environment correlations as an important strategy of CNS disease modeling using this aquatic organism.

Abstracts from the NIH Office of Research on Women's Health 2018 Annual BIRCWH Meeting – Building Interdisciplinary Research Careers in Women's Health November 28, 2018

Abstracts from the NIH Office of Research on Women's Health 2018 Annual BIRCWH Meeting – Building Interdisciplinary Research Careers in Women's Health November 28, 2018

Sex Differences in the Management of Advanced Heart Failure.

Heart failure (HF) is prevalent among women and remains a leading cause of morbidity and mortality in the United States. Currently, 3million women live with HF and the prevalence is projected to continue to increase. The purpose of this review is to highlight sex differences in the use and response to evidence-based pharmacological, device, and advanced HF therapies, as well as explore emerging areas of research in sex differences in the treatment of HF. Under-representation of women in clinical HF trials has limited our understanding of sex-related differences in the treatment and outcomes of HF. Important sex differences exist in the use of evidence-based HF therapies and clinical response among women with HF. In general, women tend to obtain the same clinical benefit from evidence-based HF drug and device therapies, but the utilization rates of guideline-directed medical therapies remain poor compared to men. Future research efforts should focus on increasing the enrollment of women in HF trials to help gain helpful insight into sex-specific differences in treatment effects and subsequent clinical outcomes.

Stable Ischemic Heart Disease in Women.

Paradoxically, although women have a lower burden of coronary atherosclerosis, they experience more symptoms, more frequent hospitalizations, and a worse prognosis compared to men. This is in part due to biological variations in pathophysiology between the two sexes, and in part related to inadequate understanding of these differences, subconscious referral bias, and suboptimal application of existing women-specific guidelines. We sought to review the contemporary literature and provide an update on risk assessment, diagnosis, and management of IHD in women. IHD in women is often secondary to diffuse non-obstructive atherosclerosis, coronary spasm, inflammation, and endothelial and microvascular dysfunction, and less commonly due to the male pattern of flow-limiting epicardial stenosis. Both IHD patterns likely represent sex-specific manifestations of the same disease process. Additionally, there is a differential expression of risk factors and symptoms between men and women. Application of male-pattern IHD risk factors and presentation to women contributes to under-recognition, under-testing, and under-treatment of IHD in women compared to men. Traditional diagnostic evaluation has focused on detection of epicardial disease, amenable to revascularization. Our improved understanding of sex-specific pathophysiology of IHD has enabled us to also develop tools for detection of microvascular disease. Advances in stress MRI, flow quantification on stress PET, and provocative invasive angiography have filled this void and offer important diagnostic and prognostic information. Despite our improved understanding of sex-specific differences in presentation, risk factors, pathophysiology, diagnostic testing, and management strategies of IHD, women with IHD continue to experience worse outcomes than men. This disparity underscores the need for improved research and understanding of biological sex differences, elimination of subconscious gender bias in referral patterns, and improved application of existing research into clinical practice.

Sex and Gender Differences Research Design for Basic, Clinical, and Population Studies: Essentials for Investigators.

A sex- and gender-informed perspective increases rigor, promotes discovery, and expands the relevance of biomedical research. In the current era of accountability to present data for males and females, thoughtful and deliberate methodology can improve study design and inference in sex and gender differences research. We address issues of motivation, subject selection, sample size, data collection, analysis, and interpretation, considering implications for basic, clinical, and population research. In particular, we focus on methods to test sex/gender differences as effect modification or interaction, and discuss why some inferences from sex-stratified data should be viewed with caution. Without careful methodology, the pursuit of sex difference research, despite a mandate from funding agencies, will result in a literature of contradiction. However, given the historic lack of attention to sex differences, the absence of evidence for sex differences is not necessarily evidence of the absence of sex differences. Thoughtfully conceived and conducted sex and gender differences research is needed to drive scientific and therapeutic discovery for all sexes and genders.

The Role of Sex and Sex Hormones in Regulating Obesity-Induced Inflammation.

Metabolic and non-metabolic complications due to obesity are becoming more prevalent, yet our understanding of the mechanisms driving these is not. This is due to individual risk factor variability making it difficult to predict disease outcomes such as diabetes and insulin resistance. Gender is a critical factor in obesity outcomes with women having more adiposity but reduced metabolic complications compared to men. The role of immune system activation during obesity is an emerging field that links adiposity to metabolic syndrome. Furthermore, evidence from animal models suggests that sex differences exist in immune responses and, therefore, could be a possible mechanism leading to sex differences in metabolic disease. While there is still much to learn in the area of sex-differences research, this chapter will review the current knowledge and literature detailing the role of sex and sex hormones on adiposity and metabolically induced inflammation in obesity.