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Abstract

Background:

Sex and gender disparities persist across biomedical research, clinical care, and health policy, despite increasing recognition of sex-specific disease mechanisms and treatment responses. Underrepresentation of women in clinical trials continues to produce male-centric treatment protocols and insufficient data to support precision care.

Methods:

This narrative review applies a translational science framework to examine recurring and cross-cutting gaps in sex and gender health science. Rather than cataloging all disease areas, the review uses three exemplar domains—mental and neurological conditions, autoimmune disorders, and cardiovascular disease—to illustrate patterns observed across the research-to-policy continuum.

Results:

Findings reveal persistent issues including underrepresentation of women in research, inadequate sex-disaggregated data, and structural biases that impede equitable evidence development. These challenges appear consistently across basic science, clinical research, guideline development, and health policy translation.

Conclusions:

To advance equitable, evidence-based care, recommendations include adopting intersectional frameworks, improving sex-disaggregated data practices, increasing investment in sex-based research, and integrating sex and gender health science into medical education. Addressing these gaps through a translational lens is essential to achieving precision medicine that effectively serves all individuals.

Keywords

women’s health gender translational science knowledge translation public health

Introduction

Translational health science provides a comprehensive framework to address sex and gender by linking discovery, clinical testing, implementation, and policy.¹ It integrates findings from basic research, clinical investigations, and population health studies to improve healthcare outcomes equitably across diverse populations.² A central challenge in women’s health is the persistent gap in translational understanding of sex differences the relative under-study of female-specific conditions.³ This narrative review uses three condition clusters as exemplars (mental/neurological, autoimmune, cardiovascular) to demonstrate generalizable translational gaps without attempting an exhausted disease inventory. We distinguish biological sex (chromosomal, hormonal, physiological) from gender (psychosocial/structural identity and roles) and examine how both shape risk, presentation, and response to treatment across the translational spectrum. Where the literature conflates terms, we note this explicitly and interpret findings cautiously. We recognize that biological, psychosocial, and societal constructs of sex and gender⁴ intersect in practice. We define sex as biological (e.g., female, male, intersex) and gender as sociocultural identity and roles. Recognizing the distinction is essential to avoid misattribution and to design appropriate interventions. Indeed, as one of the social determinants of health,⁵ gender and associated health disparities have been widely recognized but undervalued,⁶ stemming from a complex interplay of biological, social, and environmental factors that influence disease susceptibility, progression, and treatment responses. A recent workshop on women’s health research gaps at the National Institutes of Health (NIH) identified numerous female-predominant and/or specific conditions that are in desperate need of quality reformations from basic and clinical science, clinical care, workforce infrastructure, and public policy.⁶ This growing awareness has led to an emerging focus on gender medicine, “the study of how diseases differ between men and women in terms of prevention, clinical manifestation diagnostic and therapeutic approaches, prognosis, psychosocial effects, and interactions with the health-care system.”⁷,^p.237 Males and females have distinct differences in physiology and metabolism (sex differences), which may not only account for some or a portion of observed gender differences in medical disorders⁸ but also provide important insights for treatment approaches that account for differences in drug and nutrient metabolism, for example, that to date have led to serious safety issues and severe adverse drug events in women.⁹ This research bias toward men has resulted in increased events of overmedication and excess side effects in women because they are treated with dosages based on male clinical data and still underrepresented in phase 1 toxicity trials despite the NIH Revitalization Act of 1993 that requires female inclusion.¹⁰ Thus, the failure to incorporate sex-specific data in drug development has also led to adverse consequences, with women experiencing more frequent and severe medication-related side effects due to differences in pharmacokinetics and hormone metabolism.⁹ Understanding the sex differences in pharmacological responses fosters a precision medicine approach that evaluates differences in efficacy and toxicity to not only improve health but also avoid harm.¹⁰

Finally, a few conceptual frameworks provide important insights into the disparities observed in women’s health. Intersectionality¹¹ is a critical consideration when evaluating women’s health disparities in this regard. Coined by Crenshaw,¹¹ intersectionality is a framework that explains how overlapping social categories, such as race, ethnicity, gender, sexual orientation, and socioeconomic status, combine within an individual’s lived experience, mirroring broader, interconnected systems of privilege and oppression in society, including racism, sexism, and heterosexism.¹² As such, intersectionality acknowledges that constructs such as gender do not operate in isolation but intersect with race, socioeconomic status, disability, and cultural background such that outcomes are greater than the sum of their parts. Further research reveals that women from marginalized racial and ethnic groups face unique pressures, such as body image ideals, discrimination, and low sense of belonging, that can contribute to disordered eating and risky alcohol use.¹³ These intersecting cultural and structural factors exacerbate physical and mental health disparities among women. To add to this complexity, recent policy shifts, such as defunding reproductive health programs and restricting comprehensive care, have reduced access to maternal and reproductive services, especially in low- and middle-income countries.¹⁴ As such, intersectionality shapes health risks, access to care, and clinical outcomes. For example, a study by Vohra-Gupta et al.¹⁵ demonstrated that women’s access to health care is not solely influenced by individual demographic factors like race or income but by the compounded effects of intersecting identities (e.g., race/ethnicity, marital status, education, and insurance status), revealing unique patterns of disparity among subgroups. They further emphasize that addressing women’s health disparities requires an intersectional lens, as women of color, especially those uninsured or with lower socioeconomic status, face significantly heightened barriers to care due to overlapping systems of oppression and structural inequity¹⁵ and are underrepresented in clinical trials, thereby limiting biological understanding and further contributing to health inequities.¹⁶ The Superwoman Schema is another pertinent framework in this context, as it describes how many Black women internalize expectations to appear strong, suppress emotions, and prioritize caregiving and resilience, often at the expense of their own health.¹⁷ While it can foster a sense of pride and perseverance, this schema is also linked to chronic stress, delayed help-seeking, and increased risk for adverse physical and mental health outcomes.¹⁷ Transgender individuals also face multiple intersecting barriers to health care, shaped by both their gender identity and other social factors, including but not limited to fear and mistrust of providers; inconsistency in access to health care; disrespect from providers; and mistreatment due to intersecting experiences of gender, race, class, and location.¹⁸

The importance of sex and gender inclusion in research

A recent analysis from the World Economic Forum and McKinsey Health Institute¹⁹ revealed profound gender-based health disparities with significant socioeconomic implications. Their results found that women experience 25% more years in poor health compared with men, resulting in an annual loss of 75 million years due to premature mortality and morbidity.¹⁹ Notably, sex-specific conditions (e.g., endometriosis, menopause) contribute approximately 5% of women’s health burden, while 56% account for health conditions that disproportionately affect and/or manifest differently in women, further compounded by inadequate research funding and limited sex-specific data collection.¹⁹

Despite growing awareness of these differences, significant gender disparities persist in medical research. Historically, clinical trials have underrepresented or even intentionally excluded women, leading to a scarcity of sex-specific data to inform evidence-based medical guidelines and treatment protocols.^20,21 As a result, many healthcare interventions are based on male-centric data, which may not adequately address women’s health needs, as women are not simply smaller men. Clinically, the time gap between diagnosis and treatment, such as for pain relief, is longer for women, and women are more likely to experience missed and/or erroneous diagnosis for serious medical conditions.²¹ For instance, cardiovascular disease remains a leading cause of death among women, yet it is often underdiagnosed due to variable (or “non-classic”) cardiac symptom presentation that deviates from male-centered diagnostic criteria.²² Similarly, conditions such as autoimmune diseases and chronic pain syndromes, which disproportionately affect women, have historically received less research funding and clinical attention, resulting in delayed recognition and suboptimal treatment strategies.²³

Translational research plays a critical role in addressing these gaps by promoting the inclusion of sex-balanced cohorts in preclinical and many clinical studies and gender-balanced cohorts in social, behavioral, and some clinical research, and encouraging analyses that consider sex as a biological variable and gender as a psychosocial factor where appropriate. Expanding research frameworks to systematically evaluate sex and gender differences in disease mechanisms, treatment responses, and health outcomes is imperative for closing these gaps. The emphasis on adopting a precision medicine approach is an important consideration to account for sex and gender differences and ensure more personalized and effective healthcare solutions.²⁴ Additionally, integrating sex-specific analyses into clinical guidelines and training healthcare professionals to recognize sex-/gender-based variations in disease presentation and management will be crucial steps toward achieving equity in medical care.

In addition to biological factors, which will be discussed shortly, social and environmental determinants significantly contribute to gender disparities in health. Women, especially those from marginalized communities, often face substantial barriers to accessing healthcare services, preventive screenings, and timely treatment.⁶ Socioeconomic factors, cultural norms, and healthcare system biases further exacerbate these challenges. Studies have shown that healthcare providers may exhibit gender biases, leading to differential treatment approaches for men and women with similar conditions.²⁵ For instance, it has been well documented that men reporting pain are taken more seriously than women reporting pain, resulting in different prescribing practices and outcomes.^26,27 Furthermore, gender-based differences in health-seeking behaviors and the prioritization of women’s health issues in public health agendas continue to influence disparities in health outcomes.⁵

Translational science offers several strategies to address gender disparities in health care. One essential approach is the systematic integration of sex and gender considerations into research design and data analysis. Tannenbaum et al.²⁸ advocate for the development of frameworks that incorporate gender as a critical variable across all stages of research, from hypothesis generation to the implementation of findings. Additionally, effective knowledge dissemination and implementation strategies are crucial to ensuring that evidence-based interventions reach diverse populations and are incorporated into clinical practice and policy.²⁹ Community engagement initiatives, involving patients, advocacy groups, and healthcare stakeholders, can also play a pivotal role in aligning research priorities with the priorities and resources of practitioners to reflect the actual needs of individuals.²⁹

Underscoring the dynamic physiological processes that engender pathology, it is likely that the causes underlying gender and sex differences in medical disorders are multifactorial and may vary across the lifespan.⁶ Differences in hormones, hypothalamic-pituitary-adrenal (HPA)-axis activation due to stress and trauma, stress resilience and coping mechanisms, the gut microbiome, and genetics are proposed mechanisms and in need of further research.⁶ Rather than a single nidus, it is most probable that it is rather the dynamic interplay between these factors that leads to an optimal psychophysical environment for disease activation.

Sex-specific responses to early life trauma

Early life trauma (ELT) produces sex-specific neurobiological adaptations that may explain women’s heightened vulnerability to certain stress-related disorders. Research demonstrates that women are more likely than men to develop depression following ELT^30,31 and show greater susceptibility to posttraumatic stress disorder (PTSD), with younger women being particularly vulnerable.³¹

Women and men exposed to ELT develop fundamentally different patterns of HPA-axis dysregulation and autonomic nervous system function. Research examining neural responses to fear conditioning among women with PTSD has revealed that those with dissociative symptoms demonstrate significantly reduced fear-potentiated startle responses and different heart rate patterns compared with women without dissociation.³² These patterns suggest female-specific adaptations to overwhelming stress through differential modulation of the autonomic nervous system. Women with trauma histories often show evidence of emotional over-regulation, characterized by increased prefrontal cortical activity and decreased amygdala activation,³² contrasting with the under-regulated fear response more commonly observed in traumatized men. These findings help explain why trauma might manifest as different symptom profiles by sex.

Translational implications of sex and gender differences

Several structural translational gaps recur across conditions. Please see Table 1 below for a generalized translational framework for addressing disparities to accompany the following exemplar summaries to illustrate (not exhaust) how sex and gender matter and how to address gaps with generalizable actions.

Table 1.

Generalized translational framework for addressing disparities.

Translational stage	Common gaps
T0–T1: Basic discovery → clinical research	Underrepresentation of female subjects in preclinical studies Failure to analyze sex as a biological variable Limited investigation of sex-specific disease mechanisms Insufficient funding for female-specific conditions
T2: Clinical research → guidelines	Male-biased clinical trial populations Lack of sex-disaggregated outcome reporting Guidelines that fail to address sex-specific presentations Inadequate consideration of hormonal influences across the lifespan
T3: Guidelines → implementation	Provider bias in diagnosis and treatment decisions Delayed recognition of female-specific symptom presentations Inadequate training on sex and gender differences in medical education Systemic barriers to accessing appropriate care
T4: Care → policy	Policies that do not account for sex-specific needs Insufficient investment in women’s health infrastructure Lack of intersectional approaches to health equity Missing feedback loops between population data and individual care

Mental health and neurological disorders

Overview of mental and neurological health disparities

Several mental health disorders appear to demonstrate female dominance, including but not limited to anxiety,³³ depression,³⁴ eating disorders,³⁵ and bipolar disorder.³⁶ It has been suggested that women suffer more frequently from internalizing disorders such as depression, while men suffer more often from externalizing disorders such as substance abuse.⁴ Interestingly, however, some male predominant disorders have a greater impact on females when present. For example, women tend to drink less often and less volume of alcohol than men but are more susceptible to great harms at these lower levels, including liver disease, cardiomyopathy, cancer, and cognitive sequelae.³⁷

In the realm of neurological disorders, women show a greater prevalence and worse clinical course, and worse clinical outcomes in Alzheimer’s disease and related dementias,³⁸ migraines,³⁹ and stroke,⁴⁰ which carries a 50% increased risk of dementia.⁴¹ Yet, we are just beginning to explore how sex affects the physiological course of age-mediated brain diseases and whether new diagnostics generalize to both sexes.¹⁰ A recent systematic review and meta-analysis by Gorenshtein et al.⁴² also supported that women are at higher risk of the neurological symptoms associated with the post-acute sequelae of COVID-19 (a.k.a. long-COVID) than men, including “brain fog,” headaches, fatigue, depression, and anosmia, potentially related to sex differences in immune modulations (e.g., a greater antibody response, female-specific microbiome compositions, and sex hormones).

In several chronic medical diseases such as cancer, cardiovascular disease, metabolic disorders, autoimmune disorders, and neurological disorders, depression is one of the most common comorbidities.⁴³ The risk of major depression is essentially doubled in women.³⁴ Characterized by depressed mood, loss of interest or pleasure in activities, and associated physical and psychological symptoms that cause distress and impairment for at least 2 weeks,⁴⁴ major depressive disorder carries a lifetime risk of 30% for women, compared with that of 17% for men.²⁸ Depression in women may also be associated with pregnancy, which involves important hormonal changes during the perinatal period that have been associated with cognitive deficits in memory, attention, and executive function during and after pregnancy, likely due to inflammation and oxidative stress resulting in altered neuronal signaling and degeneration.⁴⁵ Depression and anxiety are also highly associated with chronic pain, and vice versa, affecting approximately 12 million adults in the United States.⁴⁶ These frequently co-occurring disorders appear to be biologically connected, as evidenced by simultaneous neuroinflammation, systemic inflammatory markers, and shared brain regions (e.g., insular cortex, prefrontal cortex, anterior cingulate, thalamus, hippocampus, and amygdala).⁴⁶

While depression is a known modifiable risk factor for dementia, psychiatric disorders in general (e.g., anxiety, depression, schizophrenia) may also be modifiable antecedents to neurodegenerative disorders and represent an underappreciated area of prevention.⁴⁷ Early life mental disorders across a variety of psychiatric conditions have not only been associated with an increased risk of dementia, but also younger dementia onset.⁴⁷ Further, depression is a comorbidity with numerous psychological and neurological disorders.⁴³

Eating disorders, such as anorexia nervosa and bulimia nervosa, are among the most lethal psychiatric disorders⁴⁸ and have a female predominance. They affect gray matter volume while symptomatic and potentially affect long-term cognitive function, even after weight restoration.⁴⁹ Aside from cardiovascular, endocrine/metabolic, hepatic, gastrointestinal, and hematologic complications, neurological complications of eating disorders often include peripheral neuropathy, ventricular enlargement, sulcal widening, and cerebral atrophy.⁵⁰ Moreover, in addition to affecting essentially every major body system with a magnitude of medical consequences, they further overlap with depression, anxiety, substance misuse, and obsessive-compulsive disorder.⁴⁹ However, this cannot be elucidated without gender equity in such research.

Key translational gaps

Translational gaps in mental and neurological health persist, in part because research on eating disorders has largely focused on females, creating a gender bias that limits the understanding of these conditions in men.^35,51 There is a need to explore how sex affects the physiological course of age-mediated brain diseases and whether new diagnostics generalize to both sexes. The connection between psychiatric disorders and neurodegenerative disorders is an underappreciated area of prevention that requires further research.

Autoimmune and chronic disorders

Overview of autoimmune and chronic disease disparities

The current estimate for individuals living with autoimmune diseases (e.g., multiple sclerosis, lupus, rheumatoid arthritis) in the United States alone is 50 million people, and four out of five are female.⁶ Autoimmune diseases that disproportionately affect women have been attributed to sex differences such as hormonal influences, immune system function, genetic factors, mitochondrial damaging toxins and viruses, and immune genes.¹⁵

Multiple sclerosis is a chronic demyelinating disorder that affects approximately 2.8 million people worldwide.⁵² Women are more highly susceptible to the development of multiple sclerosis,⁵³ but males are more likely to experience worse cognitive impairment and disability progression.

Another immune disorder characterized by multiorgan involvement affecting predominantly women is systemic lupus erythematosus, one of the most overrepresented autoimmune diseases in women, with an adult female to male ratio estimated at 9–10:1.⁵⁴ Interestingly, this is another disorder in which females have a predominant prevalence, but males have a more severe clinical manifestation, complications, and prognosis.⁵⁴

Fibromyalgia, characterized by chronic widespread musculoskeletal pain and neurocognitive symptoms (i.e., “fibro fog”),⁵⁵ has long been considered a female illness, with an estimated female predominance of 80%–96% compared with males.⁵⁶

Key translational gaps

A key translational gap in autoimmune disease is the incomplete understanding of sex-specific immune mechanisms. The social stigma of fibromyalgia being a “female illness” has led to a research bias, with a focus on women while largely ignoring men.⁵⁶ This makes it difficult to accurately determine the true prevalence and clinical presentation in men. Historically, women with fibromyalgia were often diagnosed with a psychiatric illness, while men were treated for biomedical conditions, despite there likely being a higher prevalence of mental health issues in men with the disease.^57,58

Cardiovascular disorders

Overview of cardiovascular disease disparities

Cardiovascular disorders constitute the primary cause of death worldwide and manifest differently between sexes/genders, with a male predominance of heavily calcified plaques, while females tend to exhibit less calcified plaques but increased tendency to rupture, and worse overall prognosis.⁵⁹ While mortality and prevalence remain high in males and females,⁶⁰ women experience worse short- and long-term outcomes⁶¹ as sex and gender differences remain unrecognized and unaddressed.⁶² “CVD is understudied, underdiagnosed, and undertreated in women.”⁶³,^p.701

Women are more likely to experience symptoms such as fatigue, nausea, and shortness of breath in addition to Gulati et al.⁶⁴ or rather than the classic chest pain commonly observed in men, which can result in delays in diagnosis and treatment.²² Moreover, risk factors for cardiovascular disease (CVD) also appear to vary between sexes. In addition to typical risk factors shared by both sexes (e.g., obesity, diabetes, hypertension, hyperlipidemia), women exhibit additional predisposing factors such as hormonal life events (i.e., pregnancy, menopause), cardiovascular anatomy, anxiety, and depression, along with symptoms such as nausea, shortness of breath, and chest pain.⁵⁹ To further complicate clinical matters, women with type 2 diabetes have a higher risk of cardiovascular complications yet are less likely to receive diabetes treatment and cardiovascular risk reduction guidelines than men.⁶⁵ Moreover, type 2 diabetes is associated with an estimated 50% greater probability of dementia,⁶⁶ which as previously discussed, is more prevalent in women.

Additionally, an estimated 90% of patients with takotsubo syndrome (a.k.a. broken-heart syndrome) are female, particularly postmenopausal women, which may be related to estrogen senescence and loss of its protective effects.^67,68 Up to 10% of postmenopausal women presenting with chest pain are attributed to takotsubo syndrome, especially those associated with emotional triggers, and are increasingly associated with persisting cardiovascular complications despite its previously assumed reversibility.^67,68

Key translational gaps

The distinct presentation of symptoms in women highlights a critical translational gap in the development of diagnostic tools and clinical education. There is a need to translate mechanistic insights into optimized diagnostic tools and therapies and to enhance the clinical implementation of sex-specific guidelines.

Mechanistic insights: hormones and the microbiome

Hormonal transitions across the lifespan

The female lifespan is characterized by distinct hormonal transitions that significantly influence multiple health outcomes, creating periods of both vulnerability and opportunity for brain health. Hormonal fluctuations during puberty, pregnancy, the postpartum period, and menopause interact with neurobiological systems in complex ways that extend beyond reproductive functions.^45,69 These transitions present critical periods during which hormonal changes may contribute to cognitive and physiological alterations with both immediate and long-term implications for overall health.^31,70–72

Adolescence and neurodevelopmental vulnerability

The adolescent period represents a crucial window when gonadal hormone surges coincide with significant brain maturation. The dopaminergic reward system undergoes substantial reconfiguration during this phase, creating a neurochemical environment that favors exploration and risk-taking but may temporarily compromise certain aspects of executive function.⁷² This developmental mismatch between heightened reward sensitivity and still-maturing prefrontal control systems creates a period of particular cognitive vulnerability, especially in female adolescents who may be more susceptible to stress-related disorders following ELT.³¹ Importantly, sex-specific neurobiological adaptations to stress during this critical developmental period may explain why women show greater vulnerability to certain stress-related disorders than men. For instance, certain genetic polymorphisms interact with ELT to increase PTSD risk specifically in women, possibly due to the gene’s location in an estrogen response element.³¹ These findings highlight how female adolescence represents not only a period of cognitive vulnerability but also the one where appropriate intervention could potentially alter long-term brain and overall health trajectories.

Pregnancy, postpartum, and enduring brain adaptations

The dramatic hormonal fluctuations of pregnancy and the postpartum period can significantly impact cognitive function and other health outcomes, with implications extending well beyond these life stages.⁴⁵ Notably, these unique inflection points in a woman’s life involve short-term hormonal fluctuations during pregnancy that persist to postpartum (e.g., estrogen, progesterone, oxytocin, prolactin, and cortisol) and may lead to lasting effects in some women.^73,74 In the short term, these hormonal shifts may alter memory, executive function, and neuroplasticity, including changes in hippocampal structure and stress responsiveness.⁷³ Over the long term, pregnancy-related neuroplasticity can result in lasting effects on cognitive aging, immune function, and vulnerability to neurological diseases, with reproductive history influencing risks for conditions such as Alzheimer’s disease and stroke.⁷³ These findings underscore that pregnancy induces enduring adaptations, shaping both immediate maternal behaviors and lifelong brain health trajectories.

Further, some evidence has suggested the possibility that volumetric brain changes induced by pregnancy could be permanent. For example, neuroimaging has demonstrated that gray matter volume reductions persist 6 years after parturition,⁷⁵ and this remodeling is evident decades later.⁷⁶ A recent systematic review⁷⁷ of cognitive consequences of pregnancy found that pregnancy modestly affects verbal memory and attention and the decline persists postnatally, but the authors note that many studies were low quality and findings remain debated. Furthermore, it is important to note that the dynamic remodeling of the brain during major life transition periods (e.g., adolescence, matrescence) appear to be important for social cognition and prosocial behaviors, and the vulnerabilities associated with these are far reaching in terms of well-being as well as the duration of their effect.⁷⁶ Therefore, further research in this area would be greatly beneficial for a multitude of conditions and states.

Menopause and health changes

The menopausal transition represents another critical window when fluctuating and declining ovarian hormones significantly impact health. Data from the SWAN cohort demonstrate that perimenopausal women often experience impaired cognition and learning function, isolated primarily to the transitional phase rather than after menopause is complete.⁶⁹ These changes reflect estrogen’s regulatory effects on key neurotransmitter systems (e.g., serotonin, dopamine, and acetylcholine), which are crucial for information processing and memory formation. The neurobiological basis for these alterations involves estrogen’s influence on the brain, especially regions containing high densities of estrogen receptors, for examplem, the hippocampus and prefrontal cortex.^69,78 Sleep disruptions, affecting 40%–60% of menopausal women, further compound cognitive difficulties by disrupting memory consolidation processes,^79,80 not to mention the importance of sleep in brain maintenance and repair.^81–83 The hormonal changes and sleep disruptions during this period also have broader health implications, contributing to the risk of a myriad of adverse outcomes, including obesity, diabetes, hypertension, heart disease, and depression. These findings highlight the importance of addressing cognitive symptoms during the menopausal transition both for immediate quality of life and for potential long-term brain health benefits.

The microbiota-gut-brain axis and health

Sex hormones also influence the gut microbiome in a sex-dependent manner⁸⁴ and may underlie many sex differences in pathophysiology.⁸⁵ A growing body of evidence is recognizing the microbiota-gut-immune-brain axis as a potent origin for the diagnosis, prevention, development, and treatment of a myriad of disease states.⁸⁶ We coexist with trillions of microorganisms that constitute our gut microbiota that influence health and homeostasis, or when imbalanced, dysbiosis of the microbiome is a key driver in an array of physical and psychological disorders.⁸⁷

Sex-specific microbiome-metabolism interactions

Recent evidence supports a crosstalk between the microbiome and steroid hormones, both in the synthesis and metabolism of hormones and neurotransmitters in the gut, with the host hormones influencing the composition of the microbiome and being linked to various sex-specific disorders (e.g., polycystic ovary syndrome (PCOS)).⁸⁸ Further, emerging evidence suggests that the microbiota-gut-immune-brain axis may be a key mediator of sex differences in cognitive health, with hormonal transitions influencing gut microbial composition and function, which in turn impacts neuroinflammation and cognitive processes.⁸⁹

From a clinical perspective, these cognitive vulnerabilities during hormonal transitions represent potential windows for targeted intervention. For instance, the higher prevalence of depression during perimenopause appears to interact with cognitive function, suggesting that treating mood symptoms might help preserve cognitive abilities during this transition.⁶⁹ Beyond cognition, important processes in gut microbiome functioning interact with pathways under sex hormone control (e.g., toll-like receptor signaling, flavin monooxygenase signaling) that influence factors associated with cardiovascular disease and metabolic disorders (e.g., hypertension, glucose dysregulation, dyslipidemia, obesity).⁹⁰ Sex differences in gut microbiome-driven diseases also supports its involvement in immunological, neuropsychiatric, and respiratory disorders.⁹¹ Similarly, addressing sleep disruptions during menopause could have beneficial effects on cognitive performance and overall well-being, while also mitigating the risk of a myriad of adverse health outcomes (e.g., obesity, diabetes, hypertension, heart disease, depression, etc.).⁹²

Future research must move beyond identifying cognitive changes during hormonal transitions to determining how to support optimal cognitive and somatic function throughout these periods, potentially through behavioral interventions that capitalize on periods of enhanced plasticity or through targeted pharmacological approaches that address specific cognitive vulnerabilities while accounting for sex-specific differences in drug metabolism and response.⁹

Translational implications

The emerging evidence on the microbiota-gut-brain axis and its bidirectional relationship with sex hormones presents a promising area for translational intervention. A translational approach can help bridge the gap between basic research, which identifies sex-specific microbiome differences in disease pathogenesis, and clinical practice, where these insights can be used to develop novel diagnostics and therapies. For instance, the understanding of how the gut microbiome influences pathways under sex hormone control could inform interventions for diseases like PCOS, cardiovascular disease, and metabolic disorders.⁸⁴ Furthermore, addressing sleep disruptions and other health issues during menopause, which are linked to both hormonal and microbial changes, could have broader benefits for cognitive performance and overall well-being. This underscores the need for a multidimensional, translational approach that considers the complex interactions between sex, hormones, the gut microbiome, and immune function.

Addressing translational gaps

The persistence of gender-based health disparities represent a complex translational challenge requiring systematic analysis across multiple domains of scientific inquiry and implementation. As we have reviewed, recent studies have highlighted significant disparities in both research representation and clinical outcomes for women, particularly in areas such as cardiovascular disease, neurological conditions, autoimmune disease, and mental health. The root causes of translational gaps in gender disease disparities are evident in all societal spheres, including low- and middle-income countries,⁵ and require a transdisciplinary lens to tackle multilevel complexities that perpetuate these disproportions.

Intersections of physiology, environment, trauma, socioeconomic status, and cultural and cognitive biases influence sex and gender differences in health and disease at every level of the translational spectrum, spanning basic and clinical research, clinical implementation, and public health policy.¹ Indeed, the translational pathway encounters several critical junctures where sex- and gender-specific considerations are often overlooked. Improvement in basic and translational knowledge gaps of female-specific conditions and clinical presentations across the female lifespan, along with sex and gender-specific responses to treatments, are needed to generate high-quality data to provide actionable evidence to inform clinicians.⁶ Even in the early phases of translational research, prioritizing—and ideally mandating—the inclusion of sex effects as an outcome measure is essential.¹⁰ Furthermore, future research must incorporate validated measures of gender-related variables such as social roles, identity, and relational power, particularly in behavioral and psychosocial studies where possible.⁹³

Further, the implementation gap becomes particularly evident in clinical practice. A comprehensive analysis by Markowitz⁹⁴ demonstrated how sex and gender and ethnicity biases continue to influence clinical decision-making and patient outcomes. As such, sex and gender-specific clinical presentations and associated evidence must be included in the basic medical education curriculum to better inform the incoming generation of healthcare providers and close these health disparity gaps.

Summary and recommendations

Sex and gender disparities in health arise from intersecting biological, clinical, and structural determinants that manifest at multiple stages of the translational science continuum. The literature reveals persistent underrepresentation of women in research, insufficient sex-disaggregated data, and structural biases in clinical implementation and health policy. These gaps limit the ability to generate, translate, and apply evidence that reflects the diversity of women’s experiences and needs.

From a translational science perspective, these barriers can be improved by:

Embedding sex and gender considerations at every stage of research—from basic discovery to clinical trials, implementation, and policy.

Applying intersectionality frameworks to ensure disparities are understood within the context of overlapping social identities and structural inequities.

Closing the feedback loop between research and practice through data disaggregation, bidirectional learning between clinicians and researchers, and community engagement.

Targeting funding and training to build capacity for sex- and gender-responsive research and care.

Leveraging policy and guideline reform to institutionalize equity-oriented standards.

This translational approach ensures that gaps are addressed not in isolation, but systematically across the continuum, moving from problem identification to actionable, scalable solutions that improve outcomes for all women and marginalized gender groups.

Identified gap	Stage in translational continuum	Recommended action	Potential impact
Underrepresentation of women in basic and clinical research	T0–T2 (Discovery → clinical research)	Mandate sex-balanced recruitment and sex-disaggregated reporting in funding requirements and journal publication standards	Improves generalizability and safety of interventions for women
Limited integration of intersectionality into research design	T0–T4	Incorporate frameworks from intersectionality scholarship (Crenshaw, Bowleg) in study design, analysis, and reporting	Identifies subpopulation-specific needs, informs targeted interventions
Lack of sex-specific mechanistic data for disease pathophysiology	T0–T1	Increase funding for basic science that investigates sex differences in cellular, hormonal, and immune pathways	Enables development of targeted prevention and treatment strategies
Delayed or inequitable implementation of evidence into practice	T3 (Implementation)	Develop clinical guidelines that integrate sex- and gender-specific evidence; provide training for clinicians on applying them	Reduces variation in care quality, improves patient outcomes
Structural barriers in healthcare delivery (bias, access, policy gaps)	T3–T4 (Implementation → population health)	Expand access to preventive and specialty care through equity-driven policy reform; invest in community-based delivery models	Reduces disparities in access, morbidity, and mortality
Insufficient feedback between practice and research	T3–T4	Establish practice-based research networks and real-world data systems to inform ongoing research priorities	Accelerates translation of evidence into equitable practice

Discussion

Addressing sex and gender disparities in health is a complex translational challenge requiring systematic analysis across multiple domains of scientific inquiry and implementation. The three exemplar domains (mental/neurological, autoimmune, and cardiovascular) were selected to illustrate recurring, generalizable translational gaps, rather than to serve as an exhaustive disease catalog. Our review of diverse health topics—including mental health, autoimmune disorders, and cardiovascular disease—has consistently identified several recurring themes and structural gaps that limit progress.

A primary issue is the persistent underrepresentation of women in research, particularly in clinical trials. This lack of inclusion leads to a scarcity of sex-specific data, resulting in interventions and treatment protocols that are often based on male-centric data and may not adequately address women’s needs. The problem is further compounded by systemic and unconscious biases in healthcare delivery. For instance, gender bias can lead to delayed or erroneous diagnoses and differential treatment approaches, as seen in the context of pain management and autoimmune disease. These biases, along with social and environmental determinants of health, disproportionately affect women from marginalized communities, creating heightened barriers to care.

Bridging these translational divides requires structural reform in how sex and gender are integrated into research and practice. This involves integrating sex- and gender-sensitive research methods, promoting inclusive clinical trials, implementing targeted interventions, and including gender as a research variable. This must also include proactive measures that recognize that gender-diverse and transgender individuals face unique barriers in health care, including stigma, misgendering, and a lack of provider education, which can exacerbate disparities in preventive care, mental health, and chronic disease management.⁹³

Achieving meaningful progress requires shifts in medical education, policy, and clinical practice as well. Medical training must integrate sex- and gender-based differences into curricula to equip future healthcare providers with the necessary tools to recognize and address these disparities in real-world settings. Additionally, policies mandating sex-stratified data reporting and regulatory frameworks that ensure equitable drug safety testing can further drive systemic change. Strengthening collaborations between researchers, clinicians, and policymakers will be key to translating these insights into tangible improvements in healthcare access, treatment efficacy, and patient outcomes. By embedding sex and gender considerations into every stage of the translational process—from bench to bedside to policy—healthcare systems can move closer to eliminating the longstanding gaps in women’s health and achieving true precision medicine.

Limitations

This review is intended as a narrative synthesis rather than as a systematic review, and as such, it does not include formal quality assessment or exhaustive database screening of the included literature. While every effort was made to draw from interdisciplinary, peer-reviewed sources, some relevant studies, particularly those published outside of mainstream biomedical literature, from low- and middle-income countries, or published in non-English language may have been missed. Additionally, although we aimed to distinguish between sex- and gender-based findings, the conflation of these constructs in the existing literature presents a challenge to clear categorization and interpretation. Finally, the scope of this review required selective focus on specific health domains, and therefore, it may not fully represent the breadth of conditions and disparities affecting women and gender-diverse individuals globally. Future work using systematic and scoping review methodologies will be necessary to address these gaps comprehensively.

Conclusions

Despite growing awareness of disparities in women’s health, significant translational gaps persist across research, clinical care, and public health. Our review demonstrates that a dedicated translational science approach is an essential tool for addressing these disparities, demanding a structural transformation in how sex, gender, and intersecting social determinants are integrated into research design, policy, education, and implementation. The Summary and Recommendations section serves as a practical guide for this transformation, illustrating how a translational framework systematically addressed gaps. It highlights the need to embed sex- and gender-responsive actions at every stage of the continuum, from mandating equitable research representation to leveraging policy reform. By embedding intersectionality, ensuring equitable representation, and prioritizing sex- and gender-informed approaches across the translational pipeline, the biomedical community can move toward more inclusive and effective healthcare solutions. This path requires sustained investment, methodological innovation, and interdisciplinary collaboration to close the evidence-to-practice divide and improving outcomes for all women across their lifespan.

Footnotes

Acknowledgements

None.

ORCID iDs

Alison Warren

Leigh A. Frame

Ethical Considerations

Not applicable.

Consent to Participate

Not applicable.

Consent for publication

Not applicable.

Author contributions

Alison Warren: Conceptualization; Writing—original draft; Writing—review and editing; Supervision.

Krista Garrett: Writing—review and editing; Writing—original draft.

Leigh A. Frame: Writing—review and editing; Writing—original draft; Supervision.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Not applicable.

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Disparities in women’s health and clinical considerations from a translational science perspective: A narrative review and framework for future directions

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Introduction

The importance of sex and gender inclusion in research

Sex-specific responses to early life trauma

Translational implications of sex and gender differences

Mental health and neurological disorders

Overview of mental and neurological health disparities

Key translational gaps

Autoimmune and chronic disorders

Overview of autoimmune and chronic disease disparities

Key translational gaps

Cardiovascular disorders

Overview of cardiovascular disease disparities

Key translational gaps

Mechanistic insights: hormones and the microbiome

Hormonal transitions across the lifespan

Adolescence and neurodevelopmental vulnerability

Pregnancy, postpartum, and enduring brain adaptations

Menopause and health changes

The microbiota-gut-brain axis and health

Sex-specific microbiome-metabolism interactions

Translational implications

Addressing translational gaps

Summary and recommendations

Discussion

Limitations

Conclusions

Footnotes

Acknowledgements

ORCID iDs

Ethical Considerations

Consent to Participate

Consent for publication

Author contributions

Funding

Declaration of conflicting interests

Data availability statement

References