The effects of sex and gender attributes on clinical outcomes: A systematic review

The effects of sex and gender attributes on clinical outcomes: A systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review The effects of sex and gender attributes on clinical outcomes: A systematic review Anisa Brar, Anjali Issar, Thaisa Tylinski Sant’Ana, Tatyana Mollayeva This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7077506/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Biology of Sex Differences → Version 1 posted 9 You are reading this latest preprint version Abstract Background Biological sex and sociocultural gender may influence changes in health status critical to clinical decision-making, yet scientific evidence of their effects on clinically relevant outcomes remain uncertain. We aimed to systematically review research on sex and gender effects on clinical outcomes and to assess the consistency and significance of associations between sex, gender, and clinical outcomes. Methods We searched Medline, Embase, PsycInfo, CINAHL, and Web of Science from each database’s inception to November 20, 2023, and included English language peer-reviewed research utilizing standardized measures of sex and gender attributes in adults to measure their association with clinically relevant outcomes. We performed a risk of bias assessment and certainty assessment using criteria set a priori. We created visualizations of results with links to study quality and sex and gender attributes, which facilitated certainty assessment. We reported results across sex and gender-related attributes and measures. Results Of the 12,964 unique records identified, 19 studies with a total of 643,093 participants (54% male) were included in data synthesis. Four studies measured attributes of sex (testosterone, sex-specific polygenic score), and 15 studies measured attributes of gender (gender identity, roles, and adherence to masculine norms). We observed great heterogeneity in the direction and significance of the associations, resulting in evidence of moderate certainty only for the association between testosterone level and depression, and erectile function. We regarded all other evidence as very low in certainty. Conclusion Research findings regarding the effects of sex and gender attributes on clinical outcomes is variable. However, results suggest that neither sex nor gender attributes should be ignored when investigating clinically relevant outcomes. To enhance certainty, future research should delve into sex and gender attributes concurrently, taking into account that clinical disorders are not evenly distributed among the sexes. This approach would provide needed evidence to drive precision medicine and person-centered care. PROSPERO: CRD42023456917. Funding: Global Brain Health Institute, Alzheimer’s Association, and Alzheimer’s Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23-971123); Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074). Androgyny Biological sex Clinical outcomes Femininity Gender and sex assessment Health Masculinity Sex hormones Sociocultural gender Figures Figure 1 Figure 2 Figure 3 Figure 4 Highlights • Past reviews explored the effect of sex and gender on clinically relevant outcomes in adults; however, their focus was only on binary sex or gender • To address the gap, we examined the effect of sex and gender attributes collected through standardized measurements in 643,093 adults on clinically relevant outcomes • We presented a comprehensive synthesis of associations between sex and gender attributes and 34 clinically relevant outcomes across multiple domains, including cardiovascular health, mental health, endocrine and metabolic health, reproductive and hormonal health, sexual health, among others • We regarded evidence on the association between testosterone level and depression, and erectile function, as moderate in certainty; all other evidence was very low in certainty • The results of our review have important implications for future research advancing precision medicine and person-centered care. 1. Introduction Studies of the effect of biological sex and sociocultural gender in health and disease have been ongoing for decades [ 1 , 2 ]. However, the meaning and value of these effects have been questioned, in part because quantifying the diverse attributes that comprise biological sex and sociocultural gender is complex, evolves over time, and remains challenging to capture despite the strong scientific demand to use numerical measurement in medicine and scientific research persists. As Lord Kelvin famously stated in 1883, “when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” [ 3 , 4 ]. It has also been argued that “the ability to measure a variable, no matter how indirectly, is dependent on one’s ability to define it. Unless we know what a term means, we can’t show that it exists” [ 5 ]. The Canadian Institutes of Health Research (CIHR) defines sex as a biological construct associated with physical and physiological characteristics, including chromosomes, hormones, and anatomical features, and gender as a sociocultural construct, determined by social roles, behaviors, expressions, and identities [ 6 ]. The constructs of sex and gender are not independent; they influence and shape each other, impacting health and disease outcomes of people, families, and societies at large [ 7 ]. Several reviews have explored the effect of binary sex and gender on clinical outcomes, but have reported inconsistent results [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. These discrepancies likely reflect heterogeneity in the biological sex and sociocultural characteristics of research participants within the reported binary sex and gender concepts, as well as selective samples of people with specific clinical conditions. In addition, it is not known if the meaning of gender attributes would be the same in people with differences in clinical outcomes, or those of different sexes. To our knowledge, the specific attributes of sex and gender and their associations with clinical outcomes have not been systematically reviewed. We conducted a systematic review of attributes of sex and gender in adult persons with three goals: (1) to identify and critically appraise studies that used standardized measurements to capture the effects of sex and/or gender attributes on clinically relevant outcomes; (2) to categorize sex and gender attributes, their related measures, and measures of outcomes; and (3) to examine the relevance and certainty of the associations between sex and gender attributes and clinical outcomes. 2. Methods 2.1. Protocol and registration We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guideline to conduct and report our systematic review (Supplementary Material S1). We registered the protocol with the International Prospective Register of Systematic Reviews (PROSPERO, CRD42023456917) on September 2, 2023 (Supplementary Material S2). 2.2. Search strategy We developed a search strategy (Supplementary Material S3) in collaboration with an information specialist at a large rehabilitation research-teaching hospital. The search strategy used a mix of keywords and subject headings (e.g MeSH, Emtree) combined using the Boolean operators AND and OR and applied the following concepts: (A) any gender or sexuality subject headings, (B) any gender or sexuality text words in the title or author-supplied keywords, (C) any two gender or sexuality text words in the abstract (using Ovid’s frequency operator). Search terms for the concepts were sourced from a previous review [16]. We applied a search filter to each database search to exclude pediatric studies, and search filters developed by the Canadian Agency for Drugs and Technologies in Health (CADTH), to limit our searches to observational studies. We searched MEDLINE (Ovid), Embase (Ovid), PsycInfo (Ovid), Web of Science and CINAHL (EBSCOhost) from each database’s inception in 1971, 1972, 1967, and 1961, respectively, until November 20, 2023. We exported results from each database into Endnote for duplicate removal and subsequently imported results into Covidence before the screening stage. We cross-checked the references list of all included studies. 2.3. Eligibility criteria based on PICOS framework We defined eligibility criteria for study inclusion a priori, using the PICOS framework: P (Population): human participants older than 16 years of age, of any sex (i.e., male, female, other) and any gender (i.e., man, woman, gender-diverse). I (Intervention): this was not applicable as this was a systematic review of observational studies. C (Comparisons): standardized tools, scales, measurements, or norm-referenced values to capture attributes of sex (i.e., biological attributes in humans, including chromosomes, gene expression, hormone levels and function, and reproductive/sexual anatomy), attributes of gender (i.e., the socially constructed roles, behaviors, expressions and identities of girls, women, boys, men, and gender diverse people), or attributes of both sex and gender. O (Outcomes): any clinical outcome (i.e., outcomes related to a medical diagnosis or a sign or symptom). S (Study design): observational studies of any design (i.e., quantitative, mixed methods, cohort, cross-sectional, case control). Human biology exists within the context of a dynamic and evolving social environment, which, in turn, is shaped by societal expectations based on one’s biological sex. In the studies included in this review, authors frequently used the terms for sex (male, female) and gender (men, women) interchangeably, without distinguishing between these constructs. In the absence of ability to distinguish between these terms, we opted to use the terms ‘male’ and ‘female’ to maintain consistency in data synthesis and reporting. This decision was arbitrarily set, and it should not be assumed that male = men and female = woman. 2.4. Inclusion and exclusion criteria We included studies if they met the following criteria: (i) investigated the association between a sex and/or gender attribute of adults (i.e., mean study population age ≥ 16 years) and clinically-relevant outcomes using a patient or non-patient reported measure; (ii) the sex and/or gender measure was standardized, and used at least twice in research coming from different teams of investigators; and (iii) the research was published in English in a peer-reviewed journal. We excluded studies in which the only measure of sex/gender was the self-identification of participants’ sex/gender and studies which used a sex/gender measurement tool but did not link the scores to clinically relevant outcomes. Letters to the editor, case reports, dissertations, and studies with no primary data were excluded. 2.5. Study selection process At least two reviewers, including the primary authors (AB and AI), independently assessed the titles and abstracts of the identified studies against the predetermined inclusion and exclusion criteria. In the second stage, the two primary authors (AB and AI) independently assessed the full texts of potentially relevant studies to determine their compliance with the inclusion criteria. Studies that did not meet inclusion criteria were excluded (Supplementary Material S4). The senior author reviewed the quality of the first and second levels of screening. Discrepancies in inclusion/exclusion were resolved by discussion between study authors and TM. 2.6. Data extraction Two reviewers (AB and AI) used a standardized data extraction sheet developed by the senior author to independently collect study characteristics and outcome data [17]. Data that were extracted included (i) study information (i.e., authors, publication year, country, location of research, objective, study design, inclusion/exclusion criteria, sample size); (ii) participant characteristics (i.e., age, sex and any other reported parameters relevant to analysis); (iii) sex and/or gender measures used, outcome measures, statistical analyses; and (iv) outcomes and key findings related to sex and gender. If the information was unclear, we planned to contact study authors to elaborate on the results and provide further details. The senior author (TM) checked the accuracy of data extraction. We resolved inconsistencies through group discussion. 2.7. Data synthesis Heterogeneity across PICOS characteristics precluded numerical reporting of sex and gender effects as well as pooling of risk estimates for the sex and gender variable; as such, meta-analysis in its classic form was not appropriate. We used a best-evidence synthesis approach to organized findings by tabulation and qualitative description. We grouped studies into two main categories: sex effects and gender effects, and further divided by attribute and by outcome. We extracted the effect sizes of sex and/or gender associations with clinically relevant outcomes. All attributes of sex and gender, significant and non-significant, as reported by authors, were considered associations, and not causal factors. To capture and interpret expression of sex-linked attributes and gender attributes in the results of included studies, the social variables included in the statistical analysis were monitored via PROGRESS variables; namely, place of residence, race/ethnicity/culture/language, occupation, religion, education, socioeconomic status, and social capital via family and/or other social groups. All variables studied in relation to the outcome of interest were extracted and reported in Table 1 and Figs. 2–4. 2.8. Quality and risk of bias assessment We used previously developed standardized forms to assess study quality and risk of bias [18]. Two reviewers (AB and AI) independently assessed the quality of each study using the Quality in Prognosis Studies (QUIPS) tool [18]. The quality and risk of bias assessment comprised the following steps: (1) evaluation of six bias categories, including study design, study participation, study attrition, associated factors, outcome measures/confounding account, and analysis; (2) application of a crude score to rate whether each source of bias was “+”, “-”, or not applicable (NA); and (3) categorization of each study into the following classifications: (i) excellent (“++”) when all or most of the criteria were fulfilled (i.e. allowing at most one ‘cannot determine’ or ‘not reported’); (ii) good (“+”), when half of the criteria were fulfilled; and (iii) fair (“-”), when less than half of the criteria were fulfilled (Supplementary Material S5). We discussed disagreements regarding the risk of bias among the two reviewers to reach consensus (Supplementary Material S6). We did not exclude studies based on the quality assessment, but considered quality in the data analysis, reporting, and interpretation of studies. 2.9. Sensitivity analysis We conducted sensitivity analyses to examine the consistency of associations, precision, and directness of findings as recommended by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group [19]. This approach has been used in previously published work by the senior author [20]. We visually positioned results by study outcome to evaluate the consistency of the results among the same sex and/or gender attribute, reporting significance and direction of associations (positive, negative, non-significant association). We conducted subgroup analyses based on risk of bias assessment, by category and type. This allowed us to evaluate the impact of study quality on the direction and consistency of the results. 2.10. Certainty assessment We rated the certainty of evidence based on criteria that was set a priori. We rated the certainty of the evidence as high if two or more excellent quality studies coming from different teams of investigators were concordant regarding the observed association between sex (i.e., testosterone, estrogen, etc.) or gender (i.e., femininity, masculinity, androgyny, etc.) attribute for each clinical outcome (i.e., depression, anxiety, stress, etc.) without discordant results. We assessed the certainty of evidence as moderate if two or more studies of good and/or excellent quality were concordant in their results, with a maximum of one discordant result. We assigned low certainty if at least two fair and/or good quality studies were concordant in results, with a maximum of one discordant result. In all other situations, we assessed certainty as very low. 2.11. Missing data In case of missing data, we followed guidelines to contact the primary author. In the case of duplicate publications and companion papers of a primary study, the protocol was to maximize the yield of information by the simultaneous evaluation of all available data. The original study took priority for inclusion. 3. Results 3.1. Search results Our searches identified 19,538 total unique records. After the removal of duplicates, we screened 12,964 studies and of these, 175 studies met criteria for full text review. After full text review, we identified 19 studies which met the inclusion criteria for data collection and synthesis [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Reasons for exclusion for the remaining 156 studies were recorded (Supplementary Material S4) and are displayed in the PRISMA flow diagram (Fig. 1 ). 3.2. Study characteristics The 19 studies included in this systematic review involved a total of 643,093 participants, of which 54% were male [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Ten studies included both male and female participants [ 21 , 25 , 26 , 27 , 28 , 30 , 32 , 33 , 37 , 39 ], six studies included only male participants [ 22 , 23 , 29 , 35 , 36 , 38 ], two studies included only female participants [ 24 , 34 ], and one study did not report on the binary sex of their participants [ 31 ]. The age of participants ranged from 15 years [ 27 ] to 88 years [ 33 ]. Out of 19 studies, six studies originated in the United States [ 24 , 25 , 26 , 29 , 36 , 39 ], four studies each in Canada [ 21 , 30 , 33 , 37 ] and the United Kingdom [ 27 , 28 , 34 , 35 ], and one study each in Australia [ 23 ], Finland [ 31 ], Germany [ 32 ], Italy [ 22 ], and China [ 38 ]. Nine of the 19 studies were cohort studies [ 21 , 24 , 26 , 27 , 28 , 29 , 30 , 33 , 39 ], one was a randomized controlled trial [ 36 ], and the remaining nine were cross-sectional studies [ 22 , 23 , 25 , 31 , 32 , 34 , 35 , 37 , 38 ]. Detailed characteristics of the included studies can be found in Table 1 . 3.3. Attributes of sex assessments Testosterone levels Four studies used calculated free testosterone (cFT) and total testosterone (TT) as biological attributes of sex [ 22 , 24 , 31 , 36 ], of which one study also constructed a polygenic scores (PGS) for total testosterone and free testosterone using data from the UK Biobank and FinnGen [ 31 ]. Two studies used a chemiluminescence assay to measure TT [ 22 , 31 ], and two studies measured TT using liquid chromatography-tandem mass spectrometry [ 24 , 36 ]. cFT was calculated from serum albumin and sex hormone-binding globulin values [ 22 , 24 , 31 ] or by equilibrium dialysis [ 36 ]. TT values were reported in ng/dL [ 24 , 36 ], ng/mL [ 22 ], and nmol/L [ 31 ]. cFT values were reported in pg/mL [ 22 , 24 ], ng/dL [ 36 ], and nmol/L [ 31 ]. 3.4. Attributes of gender assessments Masculinity, femininity, and androgyny traits Eleven studies assessed masculinity, femininity, and androgyny using two measurement tools: the Bem Sex Role Inventory (BSRI) and the Personal Attributes Questionnaire (PAQ) [ 21 , 25 , 26 , 27 , 28 , 30 , 32 , 33 , 34 , 37 , 39 ]. Eight studies used the BSRI to capture masculinity, femininity, and androgyny in male and female participants; five studies used the full-length version [ 25 , 28 , 33 , 34 , 37 ] and three studies used the BSRI-short form [ 21 , 27 , 30 ]. Three studies applied the PAQ to assess traits of masculinity in male and female participants [ 26 , 32 , 39 ]. Möller-Leimkühler and colleagues (2009) used the German Extended PAQ (GE-PAQ), a German version of the original tool [ 32 ]. Masculine gender roles and norms Two studies captured measures of masculine gender roles using the standardized Masculine Gender Role Discrepancy Stress Scale (MGRDSS) [ 23 , 38 ]. Two studies captured measures of masculine norms using the Conformity to Masculine Norms Inventory (CMNI) [ 29 , 35 ]. Iwamoto and colleagues (2018) used the CMNI-29 items, a modified 29-item version of the original CMNI [ 29 ]. 3.5. Outcome assessment Fourteen studies examined mental health outcomes, including depression, [ 21 , 22 , 25 , 29 , 30 , 32 , 34 , 35 , 36 , 37 , 38 , 39 ], anxiety [ 21 , 38 ], muscle dysmorphia [ 23 ], stress [ 21 ], suicidal ideation [ 27 ], and trauma symptoms [ 30 ]. Eight tools were used to measure depression: Beck Depression Inventory (BDI) [ 22 , 29 , 30 , 39 ], Center for Epidemiological Studies-Depression (CES-D) Scale [ 25 , 37 , 38 ], Depression, Anxiety and Stress Scale (DASS-21) [ 21 ], Edinburgh Postnatal Depression Scale (EPDS) [ 35 ], Patient Health Questionnaire (PHQ-9) [ 36 ], Hospital Anxiety and Depression Scale (HADS) [ 34 ], WHO-5 Wellbeing Index [ 32 ], and Gotland Scale of Male Depression (GSMD) [ 32 ]. Two tools were used to measure anxiety: DASS-21 [ 21 ] and Self-Consciousness Scale (SCS) [ 38 ]. The DASS-21 was also used to measure stress [ 21 ]. The Muscle Dysmorphic Disorder Inventory (MDDI) was used to measure muscle dysmorphia [ 23 ], and the PTSD-Civilian Checklist was used to measure trauma symptoms [ 30 ]. Two studies investigated sexual health outcomes, including erectile function [ 22 , 36 ], orgasmic function [ 22 ], and sexual function [ 36 ]. Erectile function and orgasmic function were measured using the International Index of Erectile Function (IIEF) Questionnaire [ 22 , 36 ] and sexual function was measured using the Psychosexual Daily Questionnaire (PDQ) [ 36 ]. Two studies examined cardiovascular health, with outcomes of coronary heart disease (CHD) [ 31 ], cardiac death [ 31 ], and mortality from CHD [ 28 ]. Two studies investigated endocrine and metabolic disorders, including adipose insulin resistance [ 24 ], hypothyroidism, obesity, and type 2 diabetes [ 31 ]. One study examined self-reported side effects from chronic pain medications [ 33 ]. One study investigated perceived health status, including perceived health and self-reported chest pain post-myocardial infarction [ 26 ]. One of the included studies incorporated a large number of health outcomes into its analysis, including hematologic disorders (i.e., anaemia), medication use (i.e., statin use), musculoskeletal health (i.e., osteoporosis), neurological health (i.e., stroke), reproductive and hormonal health (i.e., female and male infertility, breast cancer, prostate cancer, benign leiomyoma, ovary cysts, polycystic ovary syndrome (PCOS), hirsutism, irregular menstruation, birth complications, and postmenopausal bleeding) [ 31 ]. Associations between gender and sex attributes and outcomes are described below, and visually represented in Figs. 2 – 4 . 3.6. Relationship between sex attributes and outcomes Cardiovascular health Leinonen and colleagues (2023) reported non-significant associations between TT and free testosterone with cardiac death and with CHD in both males and females [ 31 ]. Endocrine and metabolic health Leinonen and colleagues (2023) reported non-significant relationships between free testosterone and TT levels with hypothyroidism, obesity, and type 2 diabetes in both males and females [ 31 ]. Dumesic and colleagues (2019) found that in both groups of female participants (females with PCOS and age- and body mass index (BMI)-matched controls), cFT and TT were both positively correlated with adipose-insulin resistance [ 24 ]. Hematologic disorders Leinonen and colleagues (2023) reported non-significant associations between free testosterone and TT levels with anaemia [ 31 ]. Medication use Leinonen and colleagues (2023) found that in male participants, TT had a negative association with the use of statin and free testosterone had a non-significant association with statin use [ 31 ]. Findings in female participants were non-significant [ 31 ]. Mental health Boeri and colleagues (2017) reported that participants with normal TT + low cFT and participants with low TT + low cFT had an increased occurrence of depression; they also reported that in participants with low TT + normal cFT, there was a non-significant association with depression [ 22 ]. Researchers concluded that low cFT levels independently predicted increased depression regardless of TT level, and that TT level had a non-significant association with depression [ 22 ]. Snyder and colleagues (2016) reported that in the treatment group, when the serum testosterone level was increased to within normal range for males aged 19–40 years, there was a decrease in depressive symptoms based on measurements captured by the PHQ-9 scale [ 36 ]. Musculoskeletal health Leinonen and colleagues (2023) reported that TT in male participants had a positive association with osteoporosis [ 31 ]. All other associations were non-significant [ 31 ]. Neurological health Leinonen and colleagues (2023) found non-significant associations between TT and free testosterone with stroke in both male and female participants. Reproductive and hormonal health Leinonen and colleagues (2023) investigated a number of outcomes related to reproductive and hormonal health [ 31 ]. The authors reported positive associations between both TT and free testosterone with breast cancer, hirsutism, and post-menopausal bleeding in female participants. The authors reported a positive association between TT and PCOS in females; the association with free testosterone was non-significant. Free testosterone was positively associated with prostate cancer in males and with birth complications in females; the association with TT was non-significant. The authors reported non-significant associations between TT and free testosterone with female infertility, benign leiomyoma, ovarian cysts, and irregular menstruation in female participants, and with male infertility in male participants. Sexual health Boeri and colleagues (2017) reported that participants with normal TT + low cFT and participants with low TT + low cFT had decreased erectile function and decreased orgasmic function [ 22 ]. Researchers also reported that in participants with low TT + normal cFT, there was a non-significant association with erectile function and orgasmic function, and concluded that low cFT, regardless of TT level, independently predicted decrease erectile and orgasmic function, measured with the IIEF [ 22 ]. Snyder and colleagues (2016) reported that when the serum testosterone level was increased to within normal range for males aged 19–40 years, there was a positive impact on erectile function and sexual function as measured by the IIEF and PDQ, respectively [ 36 ]. 3.7. Relationship between gender attributes and outcomes Mental health Anxiety In their sample of male and female participants, Arcand and colleagues (2023) reported non-significant associations between femininity and masculinity scores with anxiety, as measured by the DASS-21 tool [ 21 ]. Yang and colleagues Depression Gibson and colleagues (2016) reported that both high masculinity and high femininity were associated with decreased depression in male participants [ 25 ]. In female participants, high masculinity was not significantly associated with depression, but high femininity was associated with decreased depression, as mesured with the CES-D Scale [ 25 ]. In their sample of male and female participants, Arcand and colleagues (2023) reported that both femininity and masculinity had non-significant associations with depression, as scored by the DASS-21 [ 21 ]. Möller-Leimkühler and colleagues (2009) reported that both masculinity and femininity were associated with decreased depression scores, and that ‘negative masculinity’ and negative femininity, as defined and measured by the GE-PAQ, were positively associated with depression [ 32 ]. Kerr and colleagues (2021) reported that both masculinity and femininity were associated with decreased depression scores in their sample of male and female particpants [ 30 ]. Zeldow and colleagues (1987) reported that both masculinity and femininity had non-significant associations with depression [ 39 ]. Both teams of researchers measured depression scores with the BDI [ 30 , 39 ]. Stress In their sample of male and female participants, Arcand and colleagues (2023) reported non-significant associations between femininity and masculinity scores with stress, as measured by the DASS-21 [ 21 ]. Suicidal ideation Hunt and colleagues (2006) reported that in the group of male and female participants born in the 1950’s (i.e., 1950’s cohort), masculinity had a negative association with self-reported suicidal ideation; the association was non-significant for the 1930’s and 1970’s cohorts [ 27 ]. Femininity had a non-significant association with self-reported suicidal ideation in all three cohorts [ 27 ]. Trauma symptoms Kerr and colleagues (2021) reported that in a population of psychiatric hospital employees, there was no significant association between masculinity and femininity with trauma symptoms, as measured by the PTSD-CC [ 30 ]. Perceived health Helgeson (1991) reported that masculinity had a non-significant association with self-reported perceived health in the sample of male and female participants post-myocardial infarction [ 26 ]. The authors reported that masculinity was positively associated with self- reported chest pain post-myocardial infarction [ 26 ]. 3.8. Relationship between masculine gender roles & norms and outcomes Mental health Anxiety Yang and colleagues (2018) reported that in males, increased masculine role discrepancy stress was associated with increased social anxiety, which was measured using the SCS [ 38 ]. Depression Yang and colleagues (2018) reported that in males, increased masculine role discrepancy stress was associated with increased depression, as measured by the CES-D [ 38 ]. Iwamoto and colleagues (2018) found that in males who had higher adherence to the masculine norms of “playboy”, “self-reliance”, and “violence”, there was an increase in depression scores, and in males who had higher adherence to the masculine norms of “winning” and “power over women”, there was a decrease in depression scores as scored by the BDI-II [ 29 ]. Non-significant associations were reported for norms of “heterosexual presentation”, “risk-taking”, and “emotional control” [ 29 ]. Short and colleagues (2023) reported that in males, adherence to the masculine norms of “self-reliance” and “primacy of work” was correlated with an increased in post-natal depression among fathers, measured using the EPDS [ 35 ]. Non-significant associations were reported for norms of “emotional control” and “power over women” [ 35 ]. Muscle dysmorphia Cunningham and colleagues (2020) reported that in males, increased masculine discrepancy stress was associated with increased muscle dysmorphia, as scored by the MDDI [ 23 ]. 3.9. Relationship between gender attributes and outcomes with interaction terms Three studies incorporated interaction terms in their analyses, encompassing gender identity and other parameters [ 21 , 25 , 33 ]. The results of these studies are described below and were not used in the certainty assessment. Anxiety, stress, and depression Arcand and colleagues (2023) studied the interactions between binary sex (i.e., male or female), gender attributes (i.e., femininity and masculinity), and time elapsed since baseline (i.e., T 1 = 3 months, T 2 = 6 months, T 3 = 9 months, T 4 = 12 months) and how these interactions associated with depression, anxiety, and stress [ 21 ]. Researchers identified a time*sex*femininity interaction for anxiety and stress, suggesting that female participants with low femininity levels had significant higher anxiety symptoms than male participants with low femininity levels at T 4 , and that female participants with high femininity levels had significantly higher stress symptoms than male participants with high femininity at T 1 [ 21 ]. There was no significant interaction detected between these parameters for depression [ 21 ]. Gibson and colleagues (2016) investigated the interaction between binary sex (i.e., male and female), gender attributes (i.e., masculinity and femininity), and education level (i.e., college educated and non-college educated) [ 25 ]. The results of this analysis indicated a significant interaction between masculinity and education, and suggested that increased masculinity was associated with an increase in depressive symptoms in college educated female participants, and associated with a decrease in depressive symptoms in non-college educated female participants [ 25 ]. The analysis also identified that among college educated male participants, increased femininity was associated with a decrease in depression levels compared to non-college education male participants [ 25 ]. All other interactions were found to be not significant [ 25 ]. Adverse events from pain medication Nguefack and colleagues (2022) studied the interaction between participants’ gender identity (i.e., man or woman) and their gender attributes (i.e., masculinity, femininity, or androgyny), and how these parameters associated with self-reported adverse effects from pain medication [ 33 ]. Results indicated that in participants who are classified as masculine and participants who are classified as androgynous, those who identify as men reported fewer severe adverse events as compared to those who identify as women [ 33 ]. 3.10. Relationship between gender identity and outcomes with reference groups Four studies reported results in comparison to a reference group [ 28 , 33 , 34 , 37 ]. Each of the four studies used the BSRI to capture participants’ masculinity, femininity, androgyny, and undifferentiated gender scores [ 28 , 33 , 34 , 37 ]. Two studies used the undifferentiated group as a reference group in their analyses [ 33 , 34 ], one study used the androgynous group as a reference group [ 28 ], and one study used masculinity as a reference group [ 37 ]. The results of these four studies are presented below and in Fig. 4 . These results were not used in the certainty assessment. Adverse events from pain medication Nguefack and colleagues (2022) reported that androgyny (i.e., high masculinity and high femininity scores) was associated with a greater number of severe adverse effects to pain medication, in reference to participants with undifferentiated gender scores (i.e. low masculinity and low femininity scores) [ 33 ]. There was no significant association reported for participants with high masculinity nor high femininity scores [ 33 ]. This analysis was conducted in a sample of males and females; study authors excluded participants who self-identified as non-binary (n = 4) and justified this exclusion on the basis of statistical validity [ 33 ]. CHD mortality Hunt and colleagues (2007) reported that high masculinity scores in male participants was associated with an increased risk of CHD mortality, in reference to males with high androgyny scores [ 28 ]. There was no significant increase or decrease in CHD mortality risk for males with high femininity nor undifferentiated scores, in reference to males with high androgyny scores [ 28 ]. There were no statistically significant results for the analysis conducted with female participants [ 28 ]. Depression In their sample of male and female participants, Vafaei and colleagues (2016) reported that androgyny was associated with decreased prevalence rates of depression, in reference to participants with high masculinity scores [ 37 ]. There was no significant association between with high femininity nor undifferentiated scores with prevalence rates of depression, in reference to participants with high masculinity scores [ 37 ]. In their sample of female participants, Po Yee Lo and colleagues (2019) reported that masculine and androgynous traits were associated with decreased depression scores, in reference to females with undifferentiated gender scores; meanwhile, feminine traits were associated with increased depression scores [ 34 ]. 3.12. Sensitivity analysis The results of sensitivity analysis suggest that study quality may explain the variability in the direction of the associations reported. This analysis was only possible for outcomes with results from at least two studies of different study quality. Two studies of good quality [ 30 , 32 ] and two studies of fair quality [ 21 , 39 ] showed distinct results on the association between masculinity and depression. The two studies of good quality reported that higher levels of masculinity, captured using BSRI and GE-PAQ, are negatively associated with depression [ 30 , 32 ]. Möller-Leimkühler and colleagues also reported a positive association between negative masculinity, as measured by the GE-PAQ and defined as undesirable attributes such as “egoistical" and “cynical”, and depression [ 32 ]. The two studies of fair quality reported no significant association between masculinity, captured using BSRI-SF and PAQ, and depression [ 21 , 39 ]. The same four studies also investigated the association between femininity and depression. The direction of association was identical to those reported for masculinity. The two studies of good quality reported that higher levels of femininity are negatively associated with depression [ 30 , 32 ]; negative femininity, measured with two subscales “verbal passive-aggressiveness” and “excessive selflessness”, was positively associated with depression [ 32 ]. The two studies of fair quality reported no significant association between femininity and depression [ 21 , 39 ]. 3.11. Risk of bias and certainty of evidence We used the QUIPS tool to rate the studies as “excellent” (i.e., low risk of bias), “good” (i.e., moderate risk of bias, or “fair” (i.e., high risk of bias) [ 18 ]. The six potential sources for bias were scored as “Yes”, “No”, “Cannot determine”, “Not applicable”, or “Not reported”. We rated three studies as “excellent” [ 33 , 34 , 37 ], twelve studies as “good” [ 22 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 32 , 35 , 36 , 38 ], and four as “fair” quality [ 21 , 26 , 27 , 39 ] (Supplementary Material S5). We documented all sources of disagreement and decisions made (Supplementary Material S6). We observed consistent associations between testosterone level and depression, as well as testosterone and erectile function, reported by two studies of good quality [ 22 , 36 ]. Snyder et al (2016) reported that increase in serum testosterone was negatively associated with depression [ 36 ] and Boeri et al (2017) reported that low cFT was associated with increased depression [ 22 ]. For erectile function, Snyder et al (2016) reported a positive association with serum testosterone [ 36 ] and Boeri et al (2017) reported that low cFT was associated with a decrease in erectile function [ 22 ]. We considered these results to be the only ones indicative of evidence of moderate certainty. We regarded all other evidence as very low in certainty due to heterogeneity in the direction and significance of the associations between sex and gender attributes and clinical outcomes. 3.13. Missing data We did not identify any missing or unclear data and thus it was not necessary to contact the primary authors of any of our included studies. 4. Discussion In our systematic review, we synthesized scientific evidence about the relationship between sex and gender attributes and clinically relevant outcomes with the goal of identifying a set of biological and sociocultural attributes that are important for clinical and research consideration. All 19 included studies assessed the relevance of sex and gender attributes (e.g., hormone level, gender identity, and gender norms) for clinical outcomes, however, the consistency, direction, and precision of associations differed greatly. This was not unexpected given the heterogeneity observed in characteristics of research participants, types of measures used to capture sex and gender attributes, measures of outcomes, type and number of controlling variables, and statistical approaches to study associations. Testosterone level, a key hormone in reproductive and sexual health, emerged in our review as a consistent and important attribute with differing implications for the sexes [ 6 ]. Leinonen and colleagues (2023) reported positive associations between both TT and free testosterone with breast cancer, hirsutism, and post-menopausal bleeding in female participants [ 31 ]. In males, free testosterone was positively associated with prostate cancer in males [ 31 ]. Although these associations were robust after adjustment for a number of controlling variables, the authors suggested that future research should consider bidirectional associations between testosterone levels and the outcomes separately in the sexes [ 31 ]. The study by Boeri and colleagues (2017) found that participants with normal TT but low cFT, as well as those with low values for both measures, experienced significant reductions in both erectile function and orgasmic function [ 22 ], bringing attention to bioavailable testosterone and methods to precisely capture testosterone levels in the evaluation and management of sexual dysfunction. Results on cardiovascular health allow for discussion on the effect of sex attributes as well as gender. This is particularly important as the cardiovascular system is the body system most affected during the human lifespan and in response to the environment [ 40 , 41 , 42 ], including alterations in the heart rate, blood pressure, and baroreceptor physiologic control [ 43 ]. Sex differences in type and severity of arrhythmias, atherosclerosis, heart-rate variability, and disrupted sleep are well-documented [ 44 , 45 ]. In one study included in this review, authors investigated the effect of sex, particularly through testosterone level, on cardiac death and CHD but found no significant association neither in male nor female participants [ 31 ]. Hunt and colleagues (2007) investigated the effect of gender identity, and reported that among male participants, higher levels of femininity were associated with a decreased risk of CHD mortality, but not in female participants or male participants with high masculinity traits [ 28 ]. They also reported that high masculinity in male participants was associated with an increased risk of CHD mortality, in reference to androgynous males [ 28 ]. Together these results suggest that gender traits may affect cardiovascular health outcomes independently of biological sex through reactivity, coping behaviors, and interpersonal sensitivity [ 46 ], that may be protective for CHD survivorship, but further research that considers both sex and gender attributes concurrently is needed to test this hypothesis. Results of our systematic review brought attention to the cost of non-adherence to traditional masculine norms and gender role expectations, particularly when male persons are not living up to the societal standards of masculinity in Western society [ 23 , 29 , 35 , 38 ]. The results from Yang and colleagues (2018) that, in males, greater masculine role discrepancy stress was significantly associated with higher depressive symptoms [ 38 ], are consistent with the results from Iwamoto and colleagues (2018) who found that that males with higher adherence to the masculine norms of playboy, self-reliance, and violence exhibited increased depression scores [ 29 ]. Short and colleagues (2023) found that adherence to masculine norms of self-reliance and primacy of work associate with higher postnatal depression among new fathers [ 35 ], provoking discussion on the internalized distress of prioritizing work above family needs. Combined with the results of Iwamoto and colleagues (2018), that adherence to the masculine norms of winning and power over women was associated with decreased depression scores [ 29 ], and that of Yang and colleagues (2018) who found that males experiencing higher levels of masculine role discrepancy stress reported increased social anxiety [ 38 ], we highlight the complex and conflicting dimensions played by gender in the relationships between the sexes, and the conflict between societal expectations and personal identity on mental health [ 47 , 48 ]. At the same time, the role of sex attributes in mental health should not be overlooked. Findings from Syder and colleagues (2016) and Boeri and colleagues (2017) point to the association between testosterone levels in males and depression scores [ 22 , 36 ]. Taken together, these results emphasize that the processes underlying health and disease are complex, possibly shaped by a continuous interplay of biological sex through genetic, hormonal, and physiological factors, as well as sociocultural gender through roles, responsibilities, and relationships [ 7 , 49 ]. 4.1 Study limitations Heterogeneity across sample characteristics (e.g., age, sex and gender, and other factors), as well as definitions and measurements of outcomes precluded us from drawing definite conclusions, which was reflected in certainty assessment. While we observed variability in the reported associations and magnitude of effect sizes, evidence on the topic is extensive and provides a foundation on which to develop future research. In line with our protocol, we included all observational studies on the topic that used standardized measures applied by at least two different research teams, aiming to enhance comparability across studies and findings. However, many studies meeting the inclusion criteria did not apply the same measures, and the characteristics of research participants of the study samples varied greatly. This led to the exclusion of potentially relevant measures and outcomes from our review, since they were applied by only one research team. We limited our search to studies published in English, which may affect the generalizability of our findings due to omission of paper published in other languages. Despite these limitations, our review is the first comprehensive assessment of the effects of sex and gender, measured using standardized tools, on clinically relevant outcomes. 4.2 Clinical implications Our systematic review presented a comprehensive synthesis of associations between sex and gender attributes and 34 clinically relevant outcomes across multiple domains, including cardiovascular health, mental health, endocrine and metabolic health, reproductive and hormonal health, sexual health, among others. The results of our systematic review raise several important clinical questions. Should patient management strategies be tailored by gender? Is it possible that due to increased responsivity to steroid hormones, persons with mental health disorders may benefit more from psychological interventions, as opposed to pharmacotherapy? If future research addresses these important clinical questions, taking both sex and gender attributes concurrently into consideration in the clinical assessment of disorders of metabolism and reproduction, mental health disorders, and others, may very well become standard practice. 4.3 Research implications In our systematic review, we synthesized published research that used standardized measures of sex and gender attributes to study their implications in clinically relevant outcomes, as opposed to binary sex and gender. Of the 19 studies included in our review, none captured attributes of both sex and gender; each study measured either attributes of either gender or sex, but not both. Incorporating standardized measurements of both sex and gender attributes in future health research may provide a richer understanding of the role that these constructs play in clinical outcomes. We offer several recommendations to guide future research. In alignment with guidance from various health and research authorities, we emphasize incorporation of standardized measures of both biological sex and sociocultural gender attributes in research with human participants. The results would allow investigators to identify sex- and gender-specific targets, thereby seeding the pipeline with the potential to produce precision interventions. This line of research is gaining attention, particularly using big data to build gender indexes taking into account biological sex and apply them to the investigation of risks for clinical outcomes [ 49 , 50 , 51 ]. Second, future research should focus on elucidating biopsychosocial mechanisms driving differences in clinically relevant outcomes [ 52 ], in lieu of additional descriptive studies that demonstrate yet again that people are diverse in both their biology as well as their gender. This recommendation will be best served by translational approaches that take novel findings from research across health pillars, as this is a critical tenet of the biopsychosocial model that is often overlooked. Third, research should routinely include description and analyses of sex and gender attributes of their research participants, even if these findings are presented in supplementary tables. Very limited information regarding such characteristics is available in published research. Building on the existing research base by following the above recommendations holds the potential to substantively impact evidence-based care in the foreseeable future. 5. Conclusions Results from the studies we reviewed suggest that neither sex nor gender attributes should be overlooked when investigating clinically relevant outcomes. Ignoring these associations may confound interpretation of results and mask the true effects that could be subject to modification to improve outcomes. Investigating sex and gender attributes concurrently might also contribute to a better understanding of the differences that are observed disorders and diseases that disproportionately affect one sex more than others. Researchers are becoming more aware of the interactive nature of biological variables and the sociocultural environment, and their combined influence on gender identity. Such interactions are particularly important to consider when interpreting differences in the associations reported in the research included in this review, which solely focused on either sex or gender. Abbreviations BDI , Beck Depression Inventory; BMI , body mass index; BSRI , Bem Sex Role Inventory; CADTH , Canadian Agency for Drugs and Technologies in Health; CES-D , Center for Epidemiological Studies-Depression; cFT , calculated free testosterone; CHD , coronary heart disease; CIHR , Canadian Institutes of Health Research; CMNI , Conformity to Masculine Norms Inventory; DASS-21 , Depression, Anxiety and Stress Scale; EPDS , Edinburgh Postnatal Depression Scale; GE-PAQ , German Extended Personal Attributes Questionnaire; GRADE , Grading of Recommendations Assessment, Development and Evaluation; GSMD , Gotland Scale of Male Depression; HADS , Hospital Anxiety and Depression Scale; IIEF , International Index of Erectile Function; MDDI , Muscle Dysmorphic Disorder Inventory; MGRDSS , Masculine Gender Role Discrepancy Stress Scale; PAQ , Personal Attributes Questionnaire; PCOS , polycystic ovary syndrome; PDQ , Psychosexual Daily Questionnaire; PHQ-9 , Patient Health Questionnaire; PRISMA , Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PTSD-CC , Post Traumatic Stress Disorder-Civilian Checklist; PTSD , post-traumatic stress disorder; QUIPS , Quality in Prognosis Studies; SCS , Self-Consciousness Scale; TT , total testosterone; WHO-5 , World Health Organization Wellbeing Index Declarations Ethics approach and consent to participate We did not seek ethics approval, as this study did not involve primary data collection. Consent for publication All authors approved the final version of the manuscript and agree to be held accountable for all aspects of the work. Availability of data and materials The data and materials supporting the findings of this systematic review are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the Global Brain Health Institute (GBHI), Alzheimer’s Association, and Alzheimer’s Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23-971123), and in part by Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors’ contributions This review was conceptualized and designed by TM. Screening was independently performed by AB and AI. Quality appraisal, risk of bias assessment, and data extraction were performed by AB and AI. Data visualization was completed by TTS. AB, AI, and TM prepared the initial draft of the manuscript. All authors reviewed drafts of the manuscript. All authors read and approved the final manuscript. Each author significantly contributed to the research, including conception, design, data acquisition, analysis, interpretation, drafting, or critical revision of the work. Acknowledgements We would like to thank trainees of the BRIDGE Lab (bridgelab.ca), Alicia Trista Ruetas, Anahita Nikkhou, Hyejun (Ashlee) Kim, Mursal Jahed, and Teodora Prnjat, for their support with title and abstract screening. We also acknowledge and sincerely thank the Library Services at the University Health Network for conducting the searches for this systematic review. References Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero J-J, DeMeo DL, et al. 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The need for a new medical model: A challenge for biomedicine. Science 1977;196:129–36. Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1SexGenderClinical.docx S1PRISMAchecklist.docx S2PROSPERO.pdf S3Searches.docx S4ReasonsExclusion.docx S5QualityAppraisal.docx S6QualityAppraisalConsensus.docx S7TableStatistics.docx Cite Share Download PDF Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Biology of Sex Differences → Version 1 posted Editorial decision: Revision requested 19 Aug, 2025 Reviews received at journal 14 Aug, 2025 Reviews received at journal 14 Aug, 2025 Reviewers agreed at journal 20 Jul, 2025 Reviewers agreed at journal 17 Jul, 2025 Reviewers invited by journal 15 Jul, 2025 Editor assigned by journal 10 Jul, 2025 Submission checks completed at journal 10 Jul, 2025 First submitted to journal 08 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7077506","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":487099181,"identity":"22176eb8-3a36-49a5-8892-91cc423e15c2","order_by":0,"name":"Anisa Brar","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Anisa","middleName":"","lastName":"Brar","suffix":""},{"id":487099182,"identity":"009d6a1a-1bef-4f72-b7da-a948344de3e9","order_by":1,"name":"Anjali Issar","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Anjali","middleName":"","lastName":"Issar","suffix":""},{"id":487099183,"identity":"f42561da-a466-49c7-a864-bb57dd351236","order_by":2,"name":"Thaisa Tylinski Sant’Ana","email":"","orcid":"","institution":"University Health Network","correspondingAuthor":false,"prefix":"","firstName":"Thaisa","middleName":"Tylinski","lastName":"Sant’Ana","suffix":""},{"id":487099184,"identity":"e8b9a110-b3d4-47f7-8139-5afa6bcb4e24","order_by":3,"name":"Tatyana Mollayeva","email":"data:image/png;base64,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","orcid":"","institution":"University Health Network","correspondingAuthor":true,"prefix":"","firstName":"Tatyana","middleName":"","lastName":"Mollayeva","suffix":""}],"badges":[],"createdAt":"2025-07-08 18:38:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7077506/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7077506/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13293-025-00772-x","type":"published","date":"2025-12-29T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87360144,"identity":"b9aa655a-4c4e-4d15-9b2d-7c0abf00049d","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":197747,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flowchart of study selection.\u003c/p\u003e","description":"","filename":"Figure1Flowchart.png","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/4717dab9601baeb063cd5127.png"},{"id":87361405,"identity":"54aaf756-ff93-4aa9-9428-dc01b3adec83","added_by":"auto","created_at":"2025-07-23 05:52:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4253625,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between sex attribute (testosterone levels) and clinical outcome, organized by outcome. Color indicates direction of association between the sex attribute and clinical outcome: positive association (pink), negative association (blue), no statistically significant association (yellow). Bar labels indicate the author, number of PROGRESS-Plus variables controlled for in analysis, sex measure, outcome measure. Length of bars corresponds to the number of variables controlled for in analysis, categorized using the PROGRESS-Plus framework: P, place of residence; R, race; O, occupation; G, gender/sex; E, education; Ss, socioeconomic status; Sc, social capital; Plus, additional parameters. The number of Plus parameters is shown in parentheses; NR, not reported. Line style corresponds to Quality Assessment of the study: Excellent (++ , solid lines), Good (+ , dashed lines), Fair (-, dotted lines). Abbreviations: M, males; F, females.\u003c/p\u003e","description":"","filename":"Figure2SexMeasures.png","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/96186b770fcd7bef0abd8f6e.png"},{"id":87363128,"identity":"e3d4a5b4-4e53-4a00-a2ca-fe292da6baa7","added_by":"auto","created_at":"2025-07-23 06:00:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2149098,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between gender attributes and clinical outcome, organized by outcome. Color indicates direction of association between the gender attribute and clinical outcome: positive association (pink), negative association (blue), no statistically significant association (yellow). Bar labels indicate the author, number of PROGRESS-Plus variables controlled for in analysis, sex measure, outcome measure. Length of bars corresponds to the number of variables controlled for in analysis, categorized using the PROGRESS-Plus framework: P, place of residence; R, race; O, occupation; G, gender/sex; E, education; Ss, socioeconomic status; Sc, social capital; Plus, additional parameters. The number of Plus parameters is shown in parentheses; NR, not reported. Line style corresponds to Quality Assessment of the study: Excellent (++ , solid lines), Good (+ , dashed lines), Fair (-, dotted lines). Abbreviations: M, males; F, females.\u003c/p\u003e","description":"","filename":"Figure3GenderMeasures.png","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/38281deb02cf67887aba4b35.png"},{"id":87360155,"identity":"9736a984-1ff8-41b8-8d9a-9e007785c378","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1006426,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between gender attributes and clinical outcome in comparison to a reference group, organized by outcome. Color indicates direction of association between the gender attribute and clinical outcome: positive association or increased risk (pink), negative association or decreased risk (blue), no statistically significant association (yellow). Bar labels indicate the author, number of PROGRESS-Plus variables controlled for in analysis, sex measure, outcome measure. Length of bars corresponds to the number of variables controlled for in analysis, categorized using the PROGRESS-Plus framework: P, place of residence; R, race; O, occupation; G, gender/sex; E, education; Ss, socioeconomic status; Sc, social capital; Plus, additional parameters. The number of Plus parameters is shown in parentheses; NR, not reported. Line style corresponds to Quality Assessment of the study: Excellent (++ , solid lines), Good (+ , dashed lines), Fair (-, dotted lines). Abbreviations: M, males; F, females.\u003c/p\u003e","description":"","filename":"Figure4GenderRef.png","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/6b26702a67432d5980a29704.png"},{"id":99545175,"identity":"741ee34d-217a-4c48-98cc-3815a2df6773","added_by":"auto","created_at":"2026-01-05 16:00:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10660966,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/001ad9e3-793d-474e-80c0-bbfc94851942.pdf"},{"id":87360146,"identity":"6a21ade5-f2a9-46d7-bcd2-fa33afc31344","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":110408,"visible":true,"origin":"","legend":"","description":"","filename":"Table1SexGenderClinical.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/80531a74c504cf1686fc5ca6.docx"},{"id":87360159,"identity":"54514a89-3b54-4d1a-988a-eee9c0ca790b","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":280791,"visible":true,"origin":"","legend":"","description":"","filename":"S1PRISMAchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/66e1e5cedcd96040026e570c.docx"},{"id":87360150,"identity":"c87e0d87-20a7-47d5-b4e7-c0bba23368de","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":99075,"visible":true,"origin":"","legend":"","description":"","filename":"S2PROSPERO.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/5deaa82eadcd6abca28419b5.pdf"},{"id":87360152,"identity":"1b13137d-09fd-4bd9-9ec2-690e87b74992","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":29072,"visible":true,"origin":"","legend":"","description":"","filename":"S3Searches.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/4238f4909daedd9b8de3effc.docx"},{"id":87363133,"identity":"64086bcc-4531-4d0d-b2c6-d27cb60b0a49","added_by":"auto","created_at":"2025-07-23 06:00:36","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":67403,"visible":true,"origin":"","legend":"","description":"","filename":"S4ReasonsExclusion.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/3380c77382de9317879b342a.docx"},{"id":87361409,"identity":"7445b5cb-14d9-4bfc-b6a5-71508e235840","added_by":"auto","created_at":"2025-07-23 05:52:36","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":43198,"visible":true,"origin":"","legend":"","description":"","filename":"S5QualityAppraisal.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/e65c4be682dc2e41f87b7d9d.docx"},{"id":87361415,"identity":"aff85d94-4640-4b32-ac7a-54680a67e354","added_by":"auto","created_at":"2025-07-23 05:52:36","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":15140,"visible":true,"origin":"","legend":"","description":"","filename":"S6QualityAppraisalConsensus.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/9fbd9033346c1da6265d54e2.docx"},{"id":87360161,"identity":"51774cf7-a9d0-4186-8288-e943b227551a","added_by":"auto","created_at":"2025-07-23 05:44:36","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":98878,"visible":true,"origin":"","legend":"","description":"","filename":"S7TableStatistics.docx","url":"https://assets-eu.researchsquare.com/files/rs-7077506/v1/cbd7cc584e6de02ba9a415ed.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The effects of sex and gender attributes on clinical outcomes: A systematic review","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Past reviews explored the effect of sex and gender on clinically relevant outcomes in adults; however, their focus was only on binary sex or gender\u003c/p\u003e\u003cp\u003e\u0026bull; To address the gap, we examined the effect of sex and gender attributes collected through standardized measurements in 643,093 adults on clinically relevant outcomes\u003c/p\u003e\u003cp\u003e\u0026bull; We presented a comprehensive synthesis of associations between sex and gender attributes and 34 clinically relevant outcomes across multiple domains, including cardiovascular health, mental health, endocrine and metabolic health, reproductive and hormonal health, sexual health, among others\u003c/p\u003e\u003cp\u003e\u0026bull; We regarded evidence on the association between testosterone level and depression, and erectile function, as moderate in certainty; all other evidence was very low in certainty\u003c/p\u003e\u003cp\u003e \u0026bull; The results of our review have important implications for future research advancing precision medicine and person-centered care.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eStudies of the effect of biological sex and sociocultural gender in health and disease have been ongoing for decades [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, the meaning and value of these effects have been questioned, in part because quantifying the diverse attributes that comprise biological sex and sociocultural gender is complex, evolves over time, and remains challenging to capture despite the strong scientific demand to use numerical measurement in medicine and scientific research persists. As Lord Kelvin famously stated in 1883, \u0026ldquo;when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind\u0026rdquo; [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It has also been argued that \u0026ldquo;the ability to measure a variable, no matter how indirectly, is dependent on one\u0026rsquo;s ability to define it. Unless we know what a term means, we can\u0026rsquo;t show that it exists\u0026rdquo; [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe Canadian Institutes of Health Research (CIHR) defines sex as a biological construct associated with physical and physiological characteristics, including chromosomes, hormones, and anatomical features, and gender as a sociocultural construct, determined by social roles, behaviors, expressions, and identities [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The constructs of sex and gender are not independent; they influence and shape each other, impacting health and disease outcomes of people, families, and societies at large [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral reviews have explored the effect of binary sex and gender on clinical outcomes, but have reported inconsistent results [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These discrepancies likely reflect heterogeneity in the biological sex and sociocultural characteristics of research participants within the reported binary sex and gender concepts, as well as selective samples of people with specific clinical conditions. In addition, it is not known if the meaning of gender attributes would be the same in people with differences in clinical outcomes, or those of different sexes. To our knowledge, the specific attributes of sex and gender and their associations with clinical outcomes have not been systematically reviewed. We conducted a systematic review of attributes of sex and gender in adult persons with three goals: (1) to identify and critically appraise studies that used standardized measurements to capture the effects of sex and/or gender attributes on clinically relevant outcomes; (2) to categorize sex and gender attributes, their related measures, and measures of outcomes; and (3) to examine the relevance and certainty of the associations between sex and gender attributes and clinical outcomes.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003e2.1. Protocol and registration\u003c/h2\u003e\n \u003cp\u003eWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guideline to conduct and report our systematic review (Supplementary Material S1). We registered the protocol with the International Prospective Register of Systematic Reviews (PROSPERO, CRD42023456917) on September 2, 2023 (Supplementary Material S2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\"\u003e\n \u003ch2\u003e2.2. Search strategy\u003c/h2\u003e\n \u003cp\u003eWe developed a search strategy (Supplementary Material S3) in collaboration with an information specialist at a large rehabilitation research-teaching hospital. The search strategy used a mix of keywords and subject headings (e.g MeSH, Emtree) combined using the Boolean operators AND and OR and applied the following concepts: (A) any gender or sexuality subject headings, (B) any gender or sexuality text words in the title or author-supplied keywords, (C) any two gender or sexuality text words in the abstract (using Ovid’s frequency operator). Search terms for the concepts were sourced from a previous review [16]. We applied a search filter to each database search to exclude pediatric studies, and search filters developed by the Canadian Agency for Drugs and Technologies in Health (CADTH), to limit our searches to observational studies. We searched MEDLINE (Ovid), Embase (Ovid), PsycInfo (Ovid), Web of Science and CINAHL (EBSCOhost) from each database’s inception in 1971, 1972, 1967, and 1961, respectively, until November 20, 2023. We exported results from each database into Endnote for duplicate removal and subsequently imported results into Covidence before the screening stage. We cross-checked the references list of all included studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003e2.3. Eligibility criteria based on PICOS framework\u003c/h2\u003e\n \u003cp\u003eWe defined eligibility criteria for study inclusion a priori, using the PICOS framework:\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e (Population): human participants older than 16 years of age, of any sex (i.e., male, female, other) and any gender (i.e., man, woman, gender-diverse).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eI\u003c/strong\u003e (Intervention): this was not applicable as this was a systematic review of observational studies.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e (Comparisons): standardized tools, scales, measurements, or norm-referenced values to capture attributes of sex (i.e., biological attributes in humans, including chromosomes, gene expression, hormone levels and function, and reproductive/sexual anatomy), attributes of gender (i.e., the socially constructed roles, behaviors, expressions and identities of girls, women, boys, men, and gender diverse people), or attributes of both sex and gender.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eO\u003c/strong\u003e (Outcomes): any clinical outcome (i.e., outcomes related to a medical diagnosis or a sign or symptom).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eS\u003c/strong\u003e (Study design): observational studies of any design (i.e., quantitative, mixed methods, cohort, cross-sectional, case control).\u003c/p\u003e\u003cbr\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003eHuman biology exists within the context of a dynamic and evolving social environment, which, in turn, is shaped by societal expectations based on one’s biological sex. In the studies included in this review, authors frequently used the terms for sex (male, female) and gender (men, women) interchangeably, without distinguishing between these constructs. In the absence of ability to distinguish between these terms, we opted to use the terms ‘male’ and ‘female’ to maintain consistency in data synthesis and reporting. This decision was arbitrarily set, and it should not be assumed that male = men and female = woman.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\"\u003e\n \u003ch2\u003e2.4. Inclusion and exclusion criteria\u003c/h2\u003e\n \u003cp\u003eWe included studies if they met the following criteria: (i) investigated the association between a sex and/or gender attribute of adults (i.e., mean study population age ≥ 16 years) and clinically-relevant outcomes using a patient or non-patient reported measure; (ii) the sex and/or gender measure was standardized, and used at least twice in research coming from different teams of investigators; and (iii) the research was published in English in a peer-reviewed journal. We excluded studies in which the only measure of sex/gender was the self-identification of participants’ sex/gender and studies which used a sex/gender measurement tool but did not link the scores to clinically relevant outcomes. Letters to the editor, case reports, dissertations, and studies with no primary data were excluded.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003e2.5. Study selection process\u003c/h2\u003e\n \u003cp\u003eAt least two reviewers, including the primary authors (AB and AI), independently assessed the titles and abstracts of the identified studies against the predetermined inclusion and exclusion criteria. In the second stage, the two primary authors (AB and AI) independently assessed the full texts of potentially relevant studies to determine their compliance with the inclusion criteria. Studies that did not meet inclusion criteria were excluded (Supplementary Material S4). The senior author reviewed the quality of the first and second levels of screening. Discrepancies in inclusion/exclusion were resolved by discussion between study authors and TM.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003e2.6. Data extraction\u003c/h2\u003e\n \u003cp\u003eTwo reviewers (AB and AI) used a standardized data extraction sheet developed by the senior author to independently collect study characteristics and outcome data [17]. Data that were extracted included (i) study information (i.e., authors, publication year, country, location of research, objective, study design, inclusion/exclusion criteria, sample size); (ii) participant characteristics (i.e., age, sex and any other reported parameters relevant to analysis); (iii) sex and/or gender measures used, outcome measures, statistical analyses; and (iv) outcomes and key findings related to sex and gender. If the information was unclear, we planned to contact study authors to elaborate on the results and provide further details. The senior author (TM) checked the accuracy of data extraction. We resolved inconsistencies through group discussion.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003e2.7. Data synthesis\u003c/h2\u003e\n \u003cp\u003eHeterogeneity across PICOS characteristics precluded numerical reporting of sex and gender effects as well as pooling of risk estimates for the sex and gender variable; as such, meta-analysis in its classic form was not appropriate. We used a best-evidence synthesis approach to organized findings by tabulation and qualitative description. We grouped studies into two main categories: sex effects and gender effects, and further divided by attribute and by outcome. We extracted the effect sizes of sex and/or gender associations with clinically relevant outcomes. All attributes of sex and gender, significant and non-significant, as reported by authors, were considered associations, and not causal factors.\u003c/p\u003e\n \u003cp\u003eTo capture and interpret expression of sex-linked attributes and gender attributes in the results of included studies, the social variables included in the statistical analysis were monitored via PROGRESS variables; namely, place of residence, race/ethnicity/culture/language, occupation, religion, education, socioeconomic status, and social capital via family and/or other social groups. All variables studied in relation to the outcome of interest were extracted and reported in Table 1 and Figs. 2–4.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003e2.8. Quality and risk of bias assessment\u003c/h2\u003e\n \u003cp\u003eWe used previously developed standardized forms to assess study quality and risk of bias [18]. Two reviewers (AB and AI) independently assessed the quality of each study using the Quality in Prognosis Studies (QUIPS) tool [18]. The quality and risk of bias assessment comprised the following steps: (1) evaluation of six bias categories, including study design, study participation, study attrition, associated factors, outcome measures/confounding account, and analysis; (2) application of a crude score to rate whether each source of bias was “+”, “-”, or not applicable (NA); and (3) categorization of each study into the following classifications: (i) excellent (“++”) when all or most of the criteria were fulfilled (i.e. allowing at most one ‘cannot determine’ or ‘not reported’); (ii) good (“+”), when half of the criteria were fulfilled; and (iii) fair (“-”), when less than half of the criteria were fulfilled (Supplementary Material S5). We discussed disagreements regarding the risk of bias among the two reviewers to reach consensus (Supplementary Material S6). We did not exclude studies based on the quality assessment, but considered quality in the data analysis, reporting, and interpretation of studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003e2.9. Sensitivity analysis\u003c/h2\u003e\n \u003cp\u003eWe conducted sensitivity analyses to examine the consistency of associations, precision, and directness of findings as recommended by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group [19]. This approach has been used in previously published work by the senior author [20]. We visually positioned results by study outcome to evaluate the consistency of the results among the same sex and/or gender attribute, reporting significance and direction of associations (positive, negative, non-significant association).\u003c/p\u003e\n \u003cp\u003eWe conducted subgroup analyses based on risk of bias assessment, by category and type. This allowed us to evaluate the impact of study quality on the direction and consistency of the results.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003e2.10. Certainty assessment\u003c/h2\u003e\n \u003cp\u003eWe rated the certainty of evidence based on criteria that was set a priori. We rated the certainty of the evidence as high if two or more excellent quality studies coming from different teams of investigators were concordant regarding the observed association between sex (i.e., testosterone, estrogen, etc.) or gender (i.e., femininity, masculinity, androgyny, etc.) attribute for each clinical outcome (i.e., depression, anxiety, stress, etc.) without discordant results. We assessed the certainty of evidence as moderate if two or more studies of good and/or excellent quality were concordant in their results, with a maximum of one discordant result. We assigned low certainty if at least two fair and/or good quality studies were concordant in results, with a maximum of one discordant result. In all other situations, we assessed certainty as very low.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003e2.11. Missing data\u003c/h2\u003e\n \u003cp\u003eIn case of missing data, we followed guidelines to contact the primary author. In the case of duplicate publications and companion papers of a primary study, the protocol was to maximize the yield of information by the simultaneous evaluation of all available data. The original study took priority for inclusion.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Search results\u003c/h2\u003e\u003cp\u003eOur searches identified 19,538 total unique records. After the removal of duplicates, we screened 12,964 studies and of these, 175 studies met criteria for full text review.\u003c/p\u003e\u003cp\u003eAfter full text review, we identified 19 studies which met the inclusion criteria for data collection and synthesis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Reasons for exclusion for the remaining 156 studies were recorded (Supplementary Material S4) and are displayed in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Study characteristics\u003c/h2\u003e\u003cp\u003eThe 19 studies included in this systematic review involved a total of 643,093 participants, of which 54% were male [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Ten studies included both male and female participants [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], six studies included only male participants [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], two studies included only female participants [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and one study did not report on the binary sex of their participants [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The age of participants ranged from 15 years [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] to 88 years [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Out of 19 studies, six studies originated in the United States [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], four studies each in Canada [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] and the United Kingdom [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and one study each in Australia [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], Finland [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], Germany [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], Italy [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and China [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Nine of the 19 studies were cohort studies [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], one was a randomized controlled trial [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and the remaining nine were cross-sectional studies [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Detailed characteristics of the included studies can be found in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Attributes of sex assessments\u003c/h2\u003e\u003cp\u003e\u003cem\u003eTestosterone levels\u003c/em\u003e\u003c/p\u003e\u003cp\u003eFour studies used calculated free testosterone (cFT) and total testosterone (TT) as biological attributes of sex [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], of which one study also constructed a polygenic scores (PGS) for total testosterone and free testosterone using data from the UK Biobank and FinnGen [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Two studies used a chemiluminescence assay to measure TT [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and two studies measured TT using liquid chromatography-tandem mass spectrometry [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. cFT was calculated from serum albumin and sex hormone-binding globulin values [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] or by equilibrium dialysis [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. TT values were reported in ng/dL [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], ng/mL [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and nmol/L [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. cFT values were reported in pg/mL [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], ng/dL [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and nmol/L [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e3.4. Attributes of gender assessments\u003c/h2\u003e\u003cp\u003e\u003cem\u003eMasculinity, femininity, and androgyny traits\u003c/em\u003e\u003c/p\u003e\u003cp\u003eEleven studies assessed masculinity, femininity, and androgyny using two measurement tools: the Bem Sex Role Inventory (BSRI) and the Personal Attributes Questionnaire (PAQ) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Eight studies used the BSRI to capture masculinity, femininity, and androgyny in male and female participants; five studies used the full-length version [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] and three studies used the BSRI-short form [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Three studies applied the PAQ to assess traits of masculinity in male and female participants [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. M\u0026ouml;ller-Leimk\u0026uuml;hler and colleagues (2009) used the German Extended PAQ (GE-PAQ), a German version of the original tool [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eMasculine gender roles and norms\u003c/em\u003e\u003c/p\u003e\u003cp\u003eTwo studies captured measures of masculine gender roles using the standardized Masculine Gender Role Discrepancy Stress Scale (MGRDSS) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Two studies captured measures of masculine norms using the Conformity to Masculine Norms Inventory (CMNI) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Iwamoto and colleagues (2018) used the CMNI-29 items, a modified 29-item version of the original CMNI [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e3.5. Outcome assessment\u003c/h2\u003e\u003cp\u003eFourteen studies examined mental health outcomes, including depression, [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], anxiety [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], muscle dysmorphia [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], stress [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], suicidal ideation [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and trauma symptoms [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Eight tools were used to measure depression: Beck Depression Inventory (BDI) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], Center for Epidemiological Studies-Depression (CES-D) Scale [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], Depression, Anxiety and Stress Scale (DASS-21) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], Edinburgh Postnatal Depression Scale (EPDS) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], Patient Health Questionnaire (PHQ-9) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], Hospital Anxiety and Depression Scale (HADS) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], WHO-5 Wellbeing Index [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and Gotland Scale of Male Depression (GSMD) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Two tools were used to measure anxiety: DASS-21 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and Self-Consciousness Scale (SCS) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The DASS-21 was also used to measure stress [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The Muscle Dysmorphic Disorder Inventory (MDDI) was used to measure muscle dysmorphia [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and the PTSD-Civilian Checklist was used to measure trauma symptoms [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTwo studies investigated sexual health outcomes, including erectile function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], orgasmic function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and sexual function [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Erectile function and orgasmic function were measured using the International Index of Erectile Function (IIEF) Questionnaire [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] and sexual function was measured using the Psychosexual Daily Questionnaire (PDQ) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTwo studies examined cardiovascular health, with outcomes of coronary heart disease (CHD) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], cardiac death [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and mortality from CHD [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Two studies investigated endocrine and metabolic disorders, including adipose insulin resistance [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], hypothyroidism, obesity, and type 2 diabetes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. One study examined self-reported side effects from chronic pain medications [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. One study investigated perceived health status, including perceived health and self-reported chest pain post-myocardial infarction [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. One of the included studies incorporated a large number of health outcomes into its analysis, including hematologic disorders (i.e., anaemia), medication use (i.e., statin use), musculoskeletal health (i.e., osteoporosis), neurological health (i.e., stroke), reproductive and hormonal health (i.e., female and male infertility, breast cancer, prostate cancer, benign leiomyoma, ovary cysts, polycystic ovary syndrome (PCOS), hirsutism, irregular menstruation, birth complications, and postmenopausal bleeding) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Associations between gender and sex attributes and outcomes are described below, and visually represented in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e3.6. Relationship between sex attributes and outcomes\u003c/h2\u003e\u003cp\u003e\u003cem\u003eCardiovascular health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) reported non-significant associations between TT and free testosterone with cardiac death and with CHD in both males and females [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eEndocrine and metabolic health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) reported non-significant relationships between free testosterone and TT levels with hypothyroidism, obesity, and type 2 diabetes in both males and females [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Dumesic and colleagues (2019) found that in both groups of female participants (females with PCOS and age- and body mass index (BMI)-matched controls), cFT and TT were both positively correlated with adipose-insulin resistance [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eHematologic disorders\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) reported non-significant associations between free testosterone and TT levels with anaemia [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eMedication use\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) found that in male participants, TT had a negative association with the use of statin and free testosterone had a non-significant association with statin use [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Findings in female participants were non-significant [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eMental health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eBoeri and colleagues (2017) reported that participants with normal TT\u0026thinsp;+\u0026thinsp;low cFT and participants with low TT\u0026thinsp;+\u0026thinsp;low cFT had an increased occurrence of depression; they also reported that in participants with low TT\u0026thinsp;+\u0026thinsp;normal cFT, there was a non-significant association with depression [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Researchers concluded that low cFT levels independently predicted increased depression regardless of TT level, and that TT level had a non-significant association with depression [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Snyder and colleagues (2016) reported that in the treatment group, when the serum testosterone level was increased to within normal range for males aged 19\u0026ndash;40 years, there was a decrease in depressive symptoms based on measurements captured by the PHQ-9 scale [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eMusculoskeletal health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) reported that TT in male participants had a positive association with osteoporosis [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. All other associations were non-significant [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eNeurological health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) found non-significant associations between TT and free testosterone with stroke in both male and female participants.\u003c/p\u003e\u003cp\u003e\u003cem\u003eReproductive and hormonal health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eLeinonen and colleagues (2023) investigated a number of outcomes related to reproductive and hormonal health [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The authors reported positive associations between both TT and free testosterone with breast cancer, hirsutism, and post-menopausal bleeding in female participants. The authors reported a positive association between TT and PCOS in females; the association with free testosterone was non-significant. Free testosterone was positively associated with prostate cancer in males and with birth complications in females; the association with TT was non-significant. The authors reported non-significant associations between TT and free testosterone with female infertility, benign leiomyoma, ovarian cysts, and irregular menstruation in female participants, and with male infertility in male participants.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSexual health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eBoeri and colleagues (2017) reported that participants with normal TT\u0026thinsp;+\u0026thinsp;low cFT and participants with low TT\u0026thinsp;+\u0026thinsp;low cFT had decreased erectile function and decreased orgasmic function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Researchers also reported that in participants with low TT\u0026thinsp;+\u0026thinsp;normal cFT, there was a non-significant association with erectile function and orgasmic function, and concluded that low cFT, regardless of TT level, independently predicted decrease erectile and orgasmic function, measured with the IIEF [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Snyder and colleagues (2016) reported that when the serum testosterone level was increased to within normal range for males aged 19\u0026ndash;40 years, there was a positive impact on erectile function and sexual function as measured by the IIEF and PDQ, respectively [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e3.7. Relationship between gender attributes and outcomes\u003c/h2\u003e\u003cp\u003e\u003cem\u003eMental health\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAnxiety\u003c/span\u003e\u003c/p\u003e\u003cp\u003eIn their sample of male and female participants, Arcand and colleagues (2023) reported non-significant associations between femininity and masculinity scores with anxiety, as measured by the DASS-21 tool [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Yang and colleagues\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDepression\u003c/span\u003e\u003c/p\u003e\u003cp\u003eGibson and colleagues (2016) reported that both high masculinity and high femininity were associated with decreased depression in male participants [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In female participants, high masculinity was not significantly associated with depression, but high femininity was associated with decreased depression, as mesured with the CES-D Scale [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In their sample of male and female participants, Arcand and colleagues (2023) reported that both femininity and masculinity had non-significant associations with depression, as scored by the DASS-21 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. M\u0026ouml;ller-Leimk\u0026uuml;hler and colleagues (2009) reported that both masculinity and femininity were associated with decreased depression scores, and that \u0026lsquo;negative masculinity\u0026rsquo; and negative femininity, as defined and measured by the GE-PAQ, were positively associated with depression [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Kerr and colleagues (2021) reported that both masculinity and femininity were associated with decreased depression scores in their sample of male and female particpants [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Zeldow and colleagues (1987) reported that both masculinity and femininity had non-significant associations with depression [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Both teams of researchers measured depression scores with the BDI [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStress\u003c/span\u003e\u003c/p\u003e\u003cp\u003eIn their sample of male and female participants, Arcand and colleagues (2023) reported non-significant associations between femininity and masculinity scores with stress, as measured by the DASS-21 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSuicidal ideation\u003c/span\u003e\u003c/p\u003e\u003cp\u003eHunt and colleagues (2006) reported that in the group of male and female participants born in the 1950\u0026rsquo;s (i.e., 1950\u0026rsquo;s cohort), masculinity had a negative association with self-reported suicidal ideation; the association was non-significant for the 1930\u0026rsquo;s and 1970\u0026rsquo;s cohorts [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Femininity had a non-significant association with self-reported suicidal ideation in all three cohorts [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eTrauma symptoms\u003c/span\u003e\u003c/p\u003e\u003cp\u003eKerr and colleagues (2021) reported that in a population of psychiatric hospital employees, there was no significant association between masculinity and femininity with trauma symptoms, as measured by the PTSD-CC [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003ePerceived health\u003c/em\u003e\u003c/p\u003e\u003cp\u003eHelgeson (1991) reported that masculinity had a non-significant association with self-reported perceived health in the sample of male and female participants post-myocardial infarction [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The authors reported that masculinity was positively associated with self- reported chest pain post-myocardial infarction [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003e3.8. Relationship between masculine gender roles \u0026amp; norms and outcomes\u003c/h2\u003e\u003cp\u003e\u003cem\u003eMental health\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAnxiety\u003c/span\u003e\u003c/p\u003e\u003cp\u003eYang and colleagues (2018) reported that in males, increased masculine role discrepancy stress was associated with increased social anxiety, which was measured using the SCS [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDepression\u003c/span\u003e\u003c/p\u003e\u003cp\u003eYang and colleagues (2018) reported that in males, increased masculine role discrepancy stress was associated with increased depression, as measured by the CES-D [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Iwamoto and colleagues (2018) found that in males who had higher adherence to the masculine norms of \u0026ldquo;playboy\u0026rdquo;, \u0026ldquo;self-reliance\u0026rdquo;, and \u0026ldquo;violence\u0026rdquo;, there was an increase in depression scores, and in males who had higher adherence to the masculine norms of \u0026ldquo;winning\u0026rdquo; and \u0026ldquo;power over women\u0026rdquo;, there was a decrease in depression scores as scored by the BDI-II [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Non-significant associations were reported for norms of \u0026ldquo;heterosexual presentation\u0026rdquo;, \u0026ldquo;risk-taking\u0026rdquo;, and \u0026ldquo;emotional control\u0026rdquo; [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Short and colleagues (2023) reported that in males, adherence to the masculine norms of \u0026ldquo;self-reliance\u0026rdquo; and \u0026ldquo;primacy of work\u0026rdquo; was correlated with an increased in post-natal depression among fathers, measured using the EPDS [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Non-significant associations were reported for norms of \u0026ldquo;emotional control\u0026rdquo; and \u0026ldquo;power over women\u0026rdquo; [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMuscle dysmorphia\u003c/span\u003e\u003c/p\u003e\u003cp\u003eCunningham and colleagues (2020) reported that in males, increased masculine discrepancy stress was associated with increased muscle dysmorphia, as scored by the MDDI [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\u003ch2\u003e3.9. Relationship between gender attributes and outcomes with interaction terms\u003c/h2\u003e\u003cp\u003eThree studies incorporated interaction terms in their analyses, encompassing gender identity and other parameters [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The results of these studies are described below and were not used in the certainty assessment.\u003c/p\u003e\u003cp\u003e\u003cem\u003eAnxiety, stress, and depression\u003c/em\u003e\u003c/p\u003e\u003cp\u003eArcand and colleagues (2023) studied the interactions between binary sex (i.e., male or female), gender attributes (i.e., femininity and masculinity), and time elapsed since baseline (i.e., T\u003csub\u003e1\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3 months, T\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;6 months, T\u003csub\u003e3\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;9 months, T\u003csub\u003e4\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12 months) and how these interactions associated with depression, anxiety, and stress [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Researchers identified a time*sex*femininity interaction for anxiety and stress, suggesting that female participants with low femininity levels had significant higher anxiety symptoms than male participants with low femininity levels at T\u003csub\u003e4\u003c/sub\u003e, and that female participants with high femininity levels had significantly higher stress symptoms than male participants with high femininity at T\u003csub\u003e1\u003c/sub\u003e [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. There was no significant interaction detected between these parameters for depression [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Gibson and colleagues (2016) investigated the interaction between binary sex (i.e., male and female), gender attributes (i.e., masculinity and femininity), and education level (i.e., college educated and non-college educated) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The results of this analysis indicated a significant interaction between masculinity and education, and suggested that increased masculinity was associated with an increase in depressive symptoms in college educated female participants, and associated with a decrease in depressive symptoms in non-college educated female participants [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The analysis also identified that among college educated male participants, increased femininity was associated with a decrease in depression levels compared to non-college education male participants [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. All other interactions were found to be not significant [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eAdverse events from pain medication\u003c/em\u003e\u003c/p\u003e\u003cp\u003eNguefack and colleagues (2022) studied the interaction between participants\u0026rsquo; gender identity (i.e., man or woman) and their gender attributes (i.e., masculinity, femininity, or androgyny), and how these parameters associated with self-reported adverse effects from pain medication [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Results indicated that in participants who are classified as masculine and participants who are classified as androgynous, those who identify as men reported fewer severe adverse events as compared to those who identify as women [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003e3.10. Relationship between gender identity and outcomes with reference groups\u003c/h2\u003e\u003cp\u003eFour studies reported results in comparison to a reference group [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Each of the four studies used the BSRI to capture participants\u0026rsquo; masculinity, femininity, androgyny, and undifferentiated gender scores [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Two studies used the undifferentiated group as a reference group in their analyses [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], one study used the androgynous group as a reference group [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], and one study used masculinity as a reference group [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The results of these four studies are presented below and in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e. These results were not used in the certainty assessment.\u003c/p\u003e\u003cp\u003e\u003cem\u003eAdverse events from pain medication\u003c/em\u003e\u003c/p\u003e\u003cp\u003eNguefack and colleagues (2022) reported that androgyny (i.e., high masculinity \u003cem\u003eand\u003c/em\u003e high femininity scores) was associated with a greater number of severe adverse effects to pain medication, in reference to participants with undifferentiated gender scores (i.e. low masculinity \u003cem\u003eand\u003c/em\u003e low femininity scores) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. There was no significant association reported for participants with high masculinity nor high femininity scores [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This analysis was conducted in a sample of males and females; study authors excluded participants who self-identified as non-binary (n\u0026thinsp;=\u0026thinsp;4) and justified this exclusion on the basis of statistical validity [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eCHD mortality\u003c/em\u003e\u003c/p\u003e\u003cp\u003eHunt and colleagues (2007) reported that high masculinity scores in male participants was associated with an increased risk of CHD mortality, in reference to males with high androgyny scores [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. There was no significant increase or decrease in CHD mortality risk for males with high femininity nor undifferentiated scores, in reference to males with high androgyny scores [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. There were no statistically significant results for the analysis conducted with female participants [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eDepression\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn their sample of male and female participants, Vafaei and colleagues (2016) reported that androgyny was associated with decreased prevalence rates of depression, in reference to participants with high masculinity scores [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. There was no significant association between with high femininity nor undifferentiated scores with prevalence rates of depression, in reference to participants with high masculinity scores [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In their sample of female participants, Po Yee Lo and colleagues (2019) reported that masculine and androgynous traits were associated with decreased depression scores, in reference to females with undifferentiated gender scores; meanwhile, feminine traits were associated with increased depression scores [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\u003ch2\u003e3.12. Sensitivity analysis\u003c/h2\u003e\u003cp\u003eThe results of sensitivity analysis suggest that study quality may explain the variability in the direction of the associations reported. This analysis was only possible for outcomes with results from at least two studies of different study quality.\u003c/p\u003e\u003cp\u003eTwo studies of good quality [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and two studies of fair quality [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] showed distinct results on the association between masculinity and depression. The two studies of good quality reported that higher levels of masculinity, captured using BSRI and GE-PAQ, are negatively associated with depression [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. M\u0026ouml;ller-Leimk\u0026uuml;hler and colleagues also reported a positive association between negative masculinity, as measured by the GE-PAQ and defined as undesirable attributes such as \u0026ldquo;egoistical\" and \u0026ldquo;cynical\u0026rdquo;, and depression [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The two studies of fair quality reported no significant association between masculinity, captured using BSRI-SF and PAQ, and depression [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe same four studies also investigated the association between femininity and depression. The direction of association was identical to those reported for masculinity. The two studies of good quality reported that higher levels of femininity are negatively associated with depression [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]; negative femininity, measured with two subscales \u0026ldquo;verbal passive-aggressiveness\u0026rdquo; and \u0026ldquo;excessive selflessness\u0026rdquo;, was positively associated with depression [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The two studies of fair quality reported no significant association between femininity and depression [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e\u003ch2\u003e3.11. Risk of bias and certainty of evidence\u003c/h2\u003e\u003cp\u003eWe used the QUIPS tool to rate the studies as \u0026ldquo;excellent\u0026rdquo; (i.e., low risk of bias), \u0026ldquo;good\u0026rdquo; (i.e., moderate risk of bias, or \u0026ldquo;fair\u0026rdquo; (i.e., high risk of bias) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The six potential sources for bias were scored as \u0026ldquo;Yes\u0026rdquo;, \u0026ldquo;No\u0026rdquo;, \u0026ldquo;Cannot determine\u0026rdquo;, \u0026ldquo;Not applicable\u0026rdquo;, or \u0026ldquo;Not reported\u0026rdquo;. We rated three studies as \u0026ldquo;excellent\u0026rdquo; [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], twelve studies as \u0026ldquo;good\u0026rdquo; [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and four as \u0026ldquo;fair\u0026rdquo; quality [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] (Supplementary Material S5). We documented all sources of disagreement and decisions made (Supplementary Material S6).\u003c/p\u003e\u003cp\u003eWe observed consistent associations between testosterone level and depression, as well as testosterone and erectile function, reported by two studies of good quality [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Snyder et al (2016) reported that increase in serum testosterone was negatively associated with depression [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] and Boeri et al (2017) reported that low cFT was associated with increased depression [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For erectile function, Snyder et al (2016) reported a positive association with serum testosterone [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] and Boeri et al (2017) reported that low cFT was associated with a decrease in erectile function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. We considered these results to be the only ones indicative of evidence of moderate certainty.\u003c/p\u003e\u003cp\u003eWe regarded all other evidence as very low in certainty due to heterogeneity in the direction and significance of the associations between sex and gender attributes and clinical outcomes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\u003ch2\u003e3.13. Missing data\u003c/h2\u003e\u003cp\u003eWe did not identify any missing or unclear data and thus it was not necessary to contact the primary authors of any of our included studies.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn our systematic review, we synthesized scientific evidence about the relationship between sex and gender attributes and clinically relevant outcomes with the goal of identifying a set of biological and sociocultural attributes that are important for clinical and research consideration. All 19 included studies assessed the relevance of sex and gender attributes (e.g., hormone level, gender identity, and gender norms) for clinical outcomes, however, the consistency, direction, and precision of associations differed greatly. This was not unexpected given the heterogeneity observed in characteristics of research participants, types of measures used to capture sex and gender attributes, measures of outcomes, type and number of controlling variables, and statistical approaches to study associations.\u003c/p\u003e\u003cp\u003eTestosterone level, a key hormone in reproductive and sexual health, emerged in our review as a consistent and important attribute with differing implications for the sexes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Leinonen and colleagues (2023) reported positive associations between both TT and free testosterone with breast cancer, hirsutism, and post-menopausal bleeding in female participants [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In males, free testosterone was positively associated with prostate cancer in males [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Although these associations were robust after adjustment for a number of controlling variables, the authors suggested that future research should consider bidirectional associations between testosterone levels and the outcomes separately in the sexes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The study by Boeri and colleagues (2017) found that participants with normal TT but low cFT, as well as those with low values for both measures, experienced significant reductions in both erectile function and orgasmic function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], bringing attention to bioavailable testosterone and methods to precisely capture testosterone levels in the evaluation and management of sexual dysfunction.\u003c/p\u003e\u003cp\u003eResults on cardiovascular health allow for discussion on the effect of sex attributes as well as gender. This is particularly important as the cardiovascular system is the body system most affected during the human lifespan and in response to the environment [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], including alterations in the heart rate, blood pressure, and baroreceptor physiologic control [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Sex differences in type and severity of arrhythmias, atherosclerosis, heart-rate variability, and disrupted sleep are well-documented [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. In one study included in this review, authors investigated the effect of sex, particularly through testosterone level, on cardiac death and CHD but found no significant association neither in male nor female participants [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Hunt and colleagues (2007) investigated the effect of gender identity, and reported that among male participants, higher levels of femininity were associated with a decreased risk of CHD mortality, but not in female participants or male participants with high masculinity traits [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. They also reported that high masculinity in male participants was associated with an increased risk of CHD mortality, in reference to androgynous males [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Together these results suggest that gender traits may affect cardiovascular health outcomes independently of biological sex through reactivity, coping behaviors, and interpersonal sensitivity [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], that may be protective for CHD survivorship, but further research that considers both sex and gender attributes concurrently is needed to test this hypothesis.\u003c/p\u003e\u003cp\u003eResults of our systematic review brought attention to the cost of non-adherence to traditional masculine norms and gender role expectations, particularly when male persons are not living up to the societal standards of masculinity in Western society [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The results from Yang and colleagues (2018) that, in males, greater masculine role discrepancy stress was significantly associated with higher depressive symptoms [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], are consistent with the results from Iwamoto and colleagues (2018) who found that that males with higher adherence to the masculine norms of playboy, self-reliance, and violence exhibited increased depression scores [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Short and colleagues (2023) found that adherence to masculine norms of self-reliance and primacy of work associate with higher postnatal depression among new fathers [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], provoking discussion on the internalized distress of prioritizing work above family needs. Combined with the results of Iwamoto and colleagues (2018), that adherence to the masculine norms of winning and power over women was associated with decreased depression scores [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and that of Yang and colleagues (2018) who found that males experiencing higher levels of masculine role discrepancy stress reported increased social anxiety [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], we highlight the complex and conflicting dimensions played by gender in the relationships between the sexes, and the conflict between societal expectations and personal identity on mental health [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. At the same time, the role of sex attributes in mental health should not be overlooked. Findings from Syder and colleagues (2016) and Boeri and colleagues (2017) point to the association between testosterone levels in males and depression scores [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Taken together, these results emphasize that the processes underlying health and disease are complex, possibly shaped by a continuous interplay of biological sex through genetic, hormonal, and physiological factors, as well as sociocultural gender through roles, responsibilities, and relationships [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Study limitations\u003c/h2\u003e\u003cp\u003eHeterogeneity across sample characteristics (e.g., age, sex and gender, and other factors), as well as definitions and measurements of outcomes precluded us from drawing definite conclusions, which was reflected in certainty assessment. While we observed variability in the reported associations and magnitude of effect sizes, evidence on the topic is extensive and provides a foundation on which to develop future research. In line with our protocol, we included all observational studies on the topic that used standardized measures applied by at least two different research teams, aiming to enhance comparability across studies and findings. However, many studies meeting the inclusion criteria did not apply the same measures, and the characteristics of research participants of the study samples varied greatly. This led to the exclusion of potentially relevant measures and outcomes from our review, since they were applied by only one research team.\u003c/p\u003e\u003cp\u003eWe limited our search to studies published in English, which may affect the generalizability of our findings due to omission of paper published in other languages. Despite these limitations, our review is the first comprehensive assessment of the effects of sex and gender, measured using standardized tools, on clinically relevant outcomes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec30\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Clinical implications\u003c/h2\u003e\u003cp\u003e Our systematic review presented a comprehensive synthesis of associations between sex and gender attributes and 34 clinically relevant outcomes across multiple domains, including cardiovascular health, mental health, endocrine and metabolic health, reproductive and hormonal health, sexual health, among others. The results of our systematic review raise several important clinical questions. Should patient management strategies be tailored by gender? Is it possible that due to increased responsivity to steroid hormones, persons with mental health disorders may benefit more from psychological interventions, as opposed to pharmacotherapy? If future research addresses these important clinical questions, taking both sex and gender attributes concurrently into consideration in the clinical assessment of disorders of metabolism and reproduction, mental health disorders, and others, may very well become standard practice.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Research implications\u003c/h2\u003e\u003cp\u003eIn our systematic review, we synthesized published research that used standardized measures of sex and gender attributes to study their implications in clinically relevant outcomes, as opposed to binary sex and gender. Of the 19 studies included in our review, none captured attributes of both sex and gender; each study measured either attributes of either gender or sex, but not both. Incorporating standardized measurements of both sex and gender attributes in future health research may provide a richer understanding of the role that these constructs play in clinical outcomes.\u003c/p\u003e\u003cp\u003eWe offer several recommendations to guide future research. In alignment with guidance from various health and research authorities, we emphasize incorporation of standardized measures of both biological sex and sociocultural gender attributes in research with human participants. The results would allow investigators to identify sex- and gender-specific targets, thereby seeding the pipeline with the potential to produce precision interventions. This line of research is gaining attention, particularly using big data to build gender indexes taking into account biological sex and apply them to the investigation of risks for clinical outcomes [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Second, future research should focus on elucidating biopsychosocial mechanisms driving differences in clinically relevant outcomes [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], in lieu of additional descriptive studies that demonstrate yet again that people are diverse in both their biology as well as their gender. This recommendation will be best served by translational approaches that take novel findings from research across health pillars, as this is a critical tenet of the biopsychosocial model that is often overlooked. Third, research should routinely include description and analyses of sex and gender attributes of their research participants, even if these findings are presented in supplementary tables. Very limited information regarding such characteristics is available in published research. Building on the existing research base by following the above recommendations holds the potential to substantively impact evidence-based care in the foreseeable future.\u003c/p\u003e\u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eResults from the studies we reviewed suggest that neither sex nor gender attributes should be overlooked when investigating clinically relevant outcomes. Ignoring these associations may confound interpretation of results and mask the true effects that could be subject to modification to improve outcomes. Investigating sex and gender attributes concurrently might also contribute to a better understanding of the differences that are observed disorders and diseases that disproportionately affect one sex more than others. Researchers are becoming more aware of the interactive nature of biological variables and the sociocultural environment, and their combined influence on gender identity. Such interactions are particularly important to consider when interpreting differences in the associations reported in the research included in this review, which solely focused on either sex or gender.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eBDI\u003c/strong\u003e, Beck Depression Inventory; \u003cstrong\u003eBMI\u003c/strong\u003e, body mass index; \u003cstrong\u003eBSRI\u003c/strong\u003e, Bem Sex Role Inventory; \u003cstrong\u003eCADTH\u003c/strong\u003e, Canadian Agency for Drugs and Technologies in Health; \u003cstrong\u003eCES-D\u003c/strong\u003e, Center for Epidemiological Studies-Depression; \u003cstrong\u003ecFT\u003c/strong\u003e, calculated free testosterone; \u003cstrong\u003eCHD\u003c/strong\u003e, coronary heart disease; \u003cstrong\u003eCIHR\u003c/strong\u003e, Canadian Institutes of Health Research; \u003cstrong\u003eCMNI\u003c/strong\u003e, Conformity to Masculine Norms Inventory; \u003cstrong\u003eDASS-21\u003c/strong\u003e, Depression, Anxiety and Stress Scale; \u003cstrong\u003eEPDS\u003c/strong\u003e, Edinburgh Postnatal Depression Scale; \u003cstrong\u003eGE-PAQ\u003c/strong\u003e, German Extended Personal Attributes Questionnaire; \u003cstrong\u003eGRADE\u003c/strong\u003e, Grading of Recommendations Assessment, Development and Evaluation; \u003cstrong\u003eGSMD\u003c/strong\u003e, Gotland Scale of Male Depression; \u003cstrong\u003eHADS\u003c/strong\u003e, Hospital Anxiety and Depression Scale; \u003cstrong\u003eIIEF\u003c/strong\u003e, International Index of Erectile Function; \u003cstrong\u003eMDDI\u003c/strong\u003e, Muscle Dysmorphic Disorder Inventory; \u003cstrong\u003eMGRDSS\u003c/strong\u003e, Masculine Gender Role Discrepancy Stress Scale; \u003cstrong\u003ePAQ\u003c/strong\u003e, Personal Attributes Questionnaire; \u003cstrong\u003ePCOS\u003c/strong\u003e, polycystic ovary syndrome; \u003cstrong\u003ePDQ\u003c/strong\u003e, Psychosexual Daily Questionnaire; \u003cstrong\u003ePHQ-9\u003c/strong\u003e, Patient Health Questionnaire; \u003cstrong\u003ePRISMA\u003c/strong\u003e, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; \u003cstrong\u003ePTSD-CC\u003c/strong\u003e, Post Traumatic Stress Disorder-Civilian Checklist; \u003cstrong\u003ePTSD\u003c/strong\u003e, post-traumatic stress disorder; \u003cstrong\u003eQUIPS\u003c/strong\u003e, Quality in Prognosis Studies; \u003cstrong\u003eSCS\u003c/strong\u003e, Self-Consciousness Scale; \u003cstrong\u003eTT\u003c/strong\u003e, total testosterone; \u003cstrong\u003eWHO-5\u003c/strong\u003e, World Health Organization Wellbeing Index\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approach and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe did not seek ethics approval, as this study did not involve primary data collection.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors approved the final version of the manuscript and agree to be held accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data and materials supporting the findings of this systematic review are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Global Brain Health Institute (GBHI), Alzheimer\u0026rsquo;s Association, and Alzheimer\u0026rsquo;s Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23-971123), and in part by Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis review was conceptualized and designed by TM. Screening was independently performed by AB and AI. Quality appraisal, risk of bias assessment, and data extraction were performed by AB and AI. Data visualization was completed by TTS. AB, AI, and TM prepared the initial draft of the manuscript. All authors reviewed drafts of the manuscript. All authors read and approved the final manuscript. Each author significantly contributed to the research, including conception, design, data acquisition, analysis, interpretation, drafting, or critical revision of the work.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank trainees of the BRIDGE Lab (bridgelab.ca), Alicia Trista Ruetas, Anahita Nikkhou, Hyejun (Ashlee) Kim, Mursal Jahed, and Teodora Prnjat, for their support with title and abstract screening. We also acknowledge and sincerely thank the Library Services at the University Health Network for conducting the searches for this systematic review.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero J-J, DeMeo DL, et al. Sex and gender: modifiers of health, disease, and medicine. The Lancet. 2020;396:565\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eMollayeva T, Mollayeva S, Pacheco N, Colantonio A. 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Med. 2022;3:289\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eAbusnina W, Elhouderi E, Walters RW, Al-Abdouh A, Mostafa MR, Liu JL, et al. Sex differences in the clinical outcomes of patients with Takotsubo stress cardiomyopathy: A meta-analysis of observational studies. Am J Cardiol. 2024;211:316\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003eZhu S, Cheng S, Liu W, Ma J, Sun W, Xiao W, et al. Gender differences in the associations of adverse childhood experiences with depression and anxiety: A systematic review and meta-analysis. J Affect Disord. 2025;378:47\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003ePrasitlumkum N, Navaravong L, Desai A, Chewcharat P, Gandhi H, Perswani P, et al. Sex differences on outcomes of catheter ablation of ventricular tachycardia in patients with structural heart disease: A real-world systematic review and meta-analysis. Heart Rhythm O2. 2022;3:847\u0026ndash;56. \u003c/li\u003e\n\u003cli\u003eOertelt-Prigione S, Wiedmann S, Endres M, Nolte CH, Regitz-Zagrosek V, Heuschmann P. Stroke and myocardial infarction: A comparative systematic evaluation of gender-specific analysis, funding and authorship patterns in cardiovascular research. Cerebrovasc Dis. 2011;31:373\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eZhu Y, Sasmita BR, Xue Y, Jiang Y, Huang B, Luo S. Sex differences on outcomes following left atrial appendage occlusion in atrial fibrillation: A systematic review and meta‐analysis. Catheter Cardiovasc Interv. 2022;100:612\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eKhan U, Abuelazm M, Saeed A, Abdelhalem A, Badawy A, AlBarakat MM, et al. Gender disparity in clinical and management outcomes in patients with pulmonary embolism: a systematic review and meta-analysis. Bayl Univ Med Cent Proc. 2025;38:313\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eWagstaff AJ, Overvad TF, Lip GYH, Lane DA. Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis. QJM. 2014;107:955\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eSmaardijk VR, Maas AHEM, Lodder P, Kop WJ, Mommersteeg PMC. Sex and gender-stratified risks of psychological factors for adverse clinical outcomes in patients with ischemic heart disease: A systematic review and meta-analysis. Int J Cardiol. 2020;302:21\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eMollayeva T, Mollayeva S, Colantonio A. Traumatic brain injury: sex, gender and intersecting vulnerabilities. Nat Rev Neurol. 2018;14:711\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eRizvi ST, Shah JS, Shaaya S, Mollayeva T. Treating cognitive impairments in primary central nervous system infections: A systematic review of pharmacological interventions. Medicine (Baltimore). 2023;102:e34151. \u003c/li\u003e\n\u003cli\u003eHayden JA, Van Der Windt DA, Cartwright JL, C\u0026ocirc;t\u0026eacute; P, Bombardier C. Assessing Bias in Studies of Prognostic Factors. Ann Intern Med. 2013;158:280. \u003c/li\u003e\n\u003cli\u003eGuyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eChapman R, Najima S, Tylinski Sant\u0026rsquo;Ana T, Lee CCK, Filice F, Babineau J, et al. Sex differences in electrical activity of the brain during sleep: a systematic review of electroencephalographic findings across the human lifespan. Biomed Eng OnLine. 2025;24:33.\u003c/li\u003e\n\u003cli\u003eArcand M, Bilodeau-Houle A, Juster R-P, Marin M-F. Sex and gender role differences on stress, depression, and anxiety symptoms in response to the COVID-19 pandemic over time. Front Psychol. 2023;14:1166154. \u003c/li\u003e\n\u003cli\u003eBoeri L, Capogrosso P, Ventimiglia E, Cazzaniga W, Pederzoli F, Moretti D, et al. Does Calculated Free Testosterone Overcome Total Testosterone in Protecting From Sexual Symptom Impairment? Findings of a Cross-Sectional Study. J Sex Med. 2017;14:1549\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003eCunningham ML, Rodgers RF, Lavender JM, Nagata JM, Frederick D, Szabo M, et al. \u0026lsquo;Big boys don\u0026rsquo;t cry\u0026rsquo;: Examining the indirect pathway of masculinity discrepancy stress and muscle dysmorphia symptomatology through dimensions of emotion dysregulation. Body Image. 2020;34:209\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eDumesic DA, Phan JD, Leung KL, Grogan TR, Ding X, Li X, et al. Adipose Insulin Resistance in Normal-Weight Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2019;104:2171\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eGibson PA, Baker EH, Milner AN. The role of sex, gender, and education on depressive symptoms among young adults in the United States. J Affect Disord. 2016;189:306\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eHelgeson VS. The effects of masculinity and social support on recovery from myocardial infarction.: Psychosom Med. 1991;53:621\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eHunt K, Sweeting H, Keoghan M, Platt S. Sex, gender role orientation, gender role attitudes and suicidal thoughts in three generations: A general population study. Soc Psychiatry Psychiatr Epidemiol. 2006;41:641\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eHunt K, Lewars H, Emslie C, Batty GD. Decreased risk of death from coronary heart disease amongst men with higher \u0026ldquo;femininity\u0026rdquo; scores: a general population cohort study. Int J Epidemiol. 2007;36:612\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eIwamoto DK, Brady J, Kaya A, Park A. Masculinity and Depression: A Longitudinal Investigation of Multidimensional Masculine Norms Among College Men. Am J Mens Health. 2018;12:1873\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eKerr P, Barbosa Da Torre M, Gigu\u0026egrave;re C-\u0026Eacute;, Lupien SJ, Juster R-P. Occupational gender roles in relation to workplace stress, allostatic load, and mental health of psychiatric hospital workers. J Psychosom Res. 2021;142:110352. \u003c/li\u003e\n\u003cli\u003eLeinonen JT, Mars N, Lehtonen LE, Ahola-Olli A, Ruotsalainen S, Lehtim\u0026auml;ki T, et al. Genetic analyses implicate complex links between adult testosterone levels and health and disease. Commun Med. 2023;3:4. \u003c/li\u003e\n\u003cli\u003eM\u0026ouml;ller-Leimk\u0026uuml;hler AM, Y\u0026uuml;cel M. Male depression in females? J Affect Disord. 2010;121:22\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eNguefack HLN, Pag\u0026eacute; MG, Gu\u0026eacute;nette L, Blais L, Diallo M, Godbout-Parent M, et al. Gender Differences in Medication Adverse Effects Experienced by People Living With Chronic Pain. Front Pain Res. 2022;3:830153. \u003c/li\u003e\n\u003cli\u003ePo Yee Lo I, Kim YK, Small E, Chan CHY. The Gendered Self of Chinese Lesbians: Self-Esteem as a Mediator Between Gender Roles and Depression. Arch Sex Behav. 2019;48:1543\u0026ndash;54. \u003c/li\u003e\n\u003cli\u003eShort S, Davis PE, Gheyoh Ndzi E. An exploration of masculinity, social support and depression in new and experienced fathers. Midwifery. 2023;123:103715. \u003c/li\u003e\n\u003cli\u003eSnyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374:611\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eVafaei A, Ahmed T, Freire ADNF, Zunzunegui MV, Guerra RO. Depression, Sex and Gender Roles in Older Adult Populations: The International Mobility in Aging Study (IMIAS). Ginsberg SD, editor. 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Circ Res. 2012;110:1097\u0026ndash;108. \u003c/li\u003e\n\u003cli\u003eFerrari AU. Modifications of the cardiovascular system With aging. Am J Geriatr Cardiol. 2002;11:30\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eSchiweck C, Piette D, Berckmans D, Claes S, Vrieze E. Heart rate and high frequency heart rate variability during stress as biomarker for clinical depression. A systematic review. Psychol Med. 2019;49:200\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eKamkwalala A, Norrholm SD, Poole JM, Brown A, Donley S, Duncan E, et al. Dark-enhanced startle responses and heart rate variability in a traumatized civilian sample: Putative sex-specific correlates of posttraumatic stress disorder. Psychosom Med. 2012;74:153\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eNielsen MW, Stefanick ML, Peragine D, Neilands TB, Ioannidis JPA, Pilote L, et al. Gender-related variables for health research. Biol Sex Differ. 2021;12:23. \u003c/li\u003e\n\u003cli\u003eBornstein RF, Bowers KS, Bonner S. Relationships of objective and projective dependency scores to sex role orientation in college student participants. J Pers Assess. 1996;66:555\u0026ndash;68. \u003c/li\u003e\n\u003cli\u003eK\u0026ouml;rner LM, Schaper ML, Pause BM, Heil M. Parent-reports of sex-typed play preference in preschool children: Relationships to 2D:4D digit ratio and older siblings\u0026rsquo; sex. Arch Sex Behav. 2020;49:2715\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eTeterina A, Zulbayar S, Mollayeva T, Chan V, Colantonio A, Escobar M. Gender versus sex in predicting outcomes of traumatic brain injury: a cohort study utilizing large administrative databases. Sci Rep. 2023;13:18453.\u003c/li\u003e\n\u003cli\u003eBallering AV, Olde Hartman TC, Rosmalen JGM. Gender scores in epidemiological research: methods, advantages and implications. Lancet Reg Health Eur. 2024 Jun 14;43:100962.\u003c/li\u003e\n\u003cli\u003ePelletier R, Ditto B, Pilote L. A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome. Psychosom Med. 2015 Jun;77(5):517-26.\u003c/li\u003e\n\u003cli\u003eEngel GL. The need for a new medical model: A challenge for biomedicine. Science 1977;196:129\u0026ndash;36.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"biology-of-sex-differences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bosd","sideBox":"Learn more about [Biology of Sex Differences](http://bsd.biomedcentral.com)","snPcode":"13293","submissionUrl":"https://submission.nature.com/new-submission/13293/3","title":"Biology of Sex Differences","twitterHandle":"@BiologySexDiff","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Androgyny, Biological sex, Clinical outcomes, Femininity, Gender and sex assessment, Health, Masculinity, Sex hormones, Sociocultural gender","lastPublishedDoi":"10.21203/rs.3.rs-7077506/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7077506/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBiological sex and sociocultural gender may influence changes in health status critical to clinical decision-making, yet scientific evidence of their effects on clinically relevant outcomes remain uncertain. We aimed to systematically review research on sex and gender effects on clinical outcomes and to assess the consistency and significance of associations between sex, gender, and clinical outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe searched Medline, Embase, PsycInfo, CINAHL, and Web of Science from each database’s inception to November 20, 2023, and included English language peer-reviewed research utilizing standardized measures of sex and gender attributes in adults to measure their association with clinically relevant outcomes. We performed a risk of bias assessment and certainty assessment using criteria set a priori. We created visualizations of results with links to study quality and sex and gender attributes, which facilitated certainty assessment. We reported results across sex and gender-related attributes and measures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 12,964 unique records identified, 19 studies with a total of 643,093 participants (54% male) were included in data synthesis. Four studies measured attributes of sex (testosterone, sex-specific polygenic score), and 15 studies measured attributes of gender (gender identity, roles, and adherence to masculine norms). We observed great heterogeneity in the direction and significance of the associations, resulting in evidence of moderate certainty only for the association between testosterone level and depression, and erectile function. We regarded all other evidence as very low in certainty.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch findings regarding the effects of sex and gender attributes on clinical outcomes is variable. However, results suggest that neither sex nor gender attributes should be ignored when investigating clinically relevant outcomes. To enhance certainty, future research should delve into sex and gender attributes concurrently, taking into account that clinical disorders are not evenly distributed among the sexes. This approach would provide needed evidence to drive precision medicine and person-centered care.\u003c/p\u003e\n\u003cp\u003ePROSPERO: CRD42023456917. Funding: Global Brain Health Institute, Alzheimer’s Association, and Alzheimer’s Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23-971123); Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074).\u003c/p\u003e","manuscriptTitle":"The effects of sex and gender attributes on clinical outcomes: A systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 05:44:29","doi":"10.21203/rs.3.rs-7077506/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-19T20:08:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-15T02:57:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-14T08:56:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209637338454746672842853354167177244068","date":"2025-07-20T05:46:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124958585593105591050484588523459902288","date":"2025-07-17T21:30:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-15T19:29:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-10T19:10:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-10T04:51:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Biology of Sex Differences","date":"2025-07-08T18:32:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"biology-of-sex-differences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bosd","sideBox":"Learn more about [Biology of Sex Differences](http://bsd.biomedcentral.com)","snPcode":"13293","submissionUrl":"https://submission.nature.com/new-submission/13293/3","title":"Biology of Sex Differences","twitterHandle":"@BiologySexDiff","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"906dbb1d-577a-4310-be46-c95e04a6172b","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T15:58:55+00:00","versionOfRecord":{"articleIdentity":"rs-7077506","link":"https://doi.org/10.1186/s13293-025-00772-x","journal":{"identity":"biology-of-sex-differences","isVorOnly":false,"title":"Biology of Sex Differences"},"publishedOn":"2025-12-29 15:56:59","publishedOnDateReadable":"December 29th, 2025"},"versionCreatedAt":"2025-07-23 05:44:29","video":"","vorDoi":"10.1186/s13293-025-00772-x","vorDoiUrl":"https://doi.org/10.1186/s13293-025-00772-x","workflowStages":[]},"version":"v1","identity":"rs-7077506","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7077506","identity":"rs-7077506","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}