Sex and gender: modifiers of health, disease, and medicine

Franck Mauvais-Jarvis, Noel Bairey Merz, Peter J Barnes, Roberta D Brinton, Juan-Jesus Carrero, Dawn L DeMeo, Geert J De Vries, C Neill Epperson, Ramaswamy Govindan, Sabra L Klein, Amedeo Lonardo, Pauline M Maki, Louise D McCullough, Vera Regitz-Zagrosek, Judith G Regensteiner, Joshua B Rubin, Kathryn Sandberg, Ayako Suzuki, Franck Mauvais-Jarvis, Noel Bairey Merz, Peter J Barnes, Roberta D Brinton, Juan-Jesus Carrero, Dawn L DeMeo, Geert J De Vries, C Neill Epperson, Ramaswamy Govindan, Sabra L Klein, Amedeo Lonardo, Pauline M Maki, Louise D McCullough, Vera Regitz-Zagrosek, Judith G Regensteiner, Joshua B Rubin, Kathryn Sandberg, Ayako Suzuki

Abstract

Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Genetic causes of sex differences (A) Genetic sex differences start with cells carrying either XX or XY chromosome complement (eg, genes outside the testis-determining SRY gene), which generates ubiquitous sex differences in the molecular makeup of all male and female cells. (B) Random inactivation of one X chromosome in female cells causes another level of sex differences in gene expression. Some X-linked genes escape inactivation in female individuals and have a higher expression in female than male individuals. (C) The Y chromosomal SRY gene directs the development of a testis in male individuals, which produces a surge of testicular testosterone at the end of pregnancy. The testosterone surge programmes cellular gene expression and tissue structure in multiple organs of male individuals via epigenetic remodelling. The combination of these genetic and developmental events programmes sex differences in physiology and susceptibility to diseases that will manifest in adulthood.
Figure 2
Figure 2
Inter-relation between sex and gender in health, diseases, and medicine Biological sex causes sex differences through genetic and hormonal influences in disease pathophysiology, clinical manifestations, and response to treatment. Sex also influences behaviours (towards more aggressive or caring phenotypes). On the other hand, gender-related behaviours (eg, smoking, lifestyle, perceived stress, and nutritional habits) produce epigenetic modifications that modulate the expression of biological sex. Gender constructs determine patients' perception of disease, help-seeking behaviour, and individual use of health care. Gender constructs also influence decision making and trigger different therapeutic responses from providers, biased by gender.
Figure 3
Figure 3
Percent distribution of the ten leading causes of death, by sex: USA, 2017 Adapted from Heron. CPD=chronic pulmonary disease.
Figure 4
Figure 4
Disabling disorders with high sex influence on prevalence For each disease, bars represent the prevalence (%) in male individuals and female individuals.
Figure 5
Figure 5
Summary of recommendations to promote sex and gender equity in the biomedical enterprise

References

    1. Clayton JA. Studying both sexes: a guiding principle for biomedicine. FASEB J. 2016;30:519–524.
    1. Schiebinger L, Leopold SS, Miller VM. Editorial policies for sex and gender analysis. Lancet. 2016;388:2841–2842.
    1. Geller SE, Koch AR, Roesch P, Filut A, Hallgren E, Carnes M. The more things change, the more they stay the same: a study to evaluate compliance with inclusion and assessment of women and minorities in randomized controlled trials. Acad Med. 2018;93:630–635.
    1. Klein SL, Schiebinger L, Stefanick ML, et al. Opinion: sex inclusion in basic research drives discovery. Proc Natl Acad Sci USA. 2015;112:5257–5258.
    1. Danska JS. Sex matters for mechanism. Sci Transl Med. 2014;6
    1. Mauvais-Jarvis F, Arnold AP, Reue K. A Guide for the design of pre-clinical studies on sex differences in metabolism. Cell Metab. 2017;25:1216–1230.
    1. GAO. U.S. Government Accountability Office Most drugs withdrawn in recent years had greater health risks for women. 2001.
    1. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509:282–283.
    1. Arnold AP. A general theory of sexual differentiation. J Neurosci Res. 2017;95:291–300.
    1. Baran Y, Subramaniam M, Biton A, et al. The landscape of genomic imprinting across diverse adult human tissues. Genome Res. 2015;25:927–936.
    1. Morris JA, Jordan CL, Breedlove SM. Sexual differentiation of the vertebrate nervous system. Nat Neurosci. 2004;7:1034–1039.
    1. McCarthy MM, Auger AP, Bale TL, et al. The epigenetics of sex differences in the brain. J Neurosci. 2009;29:12815–12823.
    1. Shannon G, Jansen M, Williams K, et al. Gender equality in science, medicine, and global health: where are we at and why does it matter? Lancet. 2019;393:560–569.
    1. Pelletier R, Choi J, Winters N, et al. Sex differences in clinical outcomes after premature acute coronary syndrome. Can J Cardiol. 2016;32:1447–1453.
    1. Pelletier 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;77:517–526.
    1. Phillips SP. Defining and measuring gender: a social determinant of health whose time has come. Int J Equity Health. 2005;4:11.
    1. Johnson JL, Greaves L, Repta R. Better science with sex and gender: facilitating the use of a sex and gender-based analysis in health research. Int J Equity Health. 2009;8:14.
    1. Regitz-Zagrosek V, Oertelt-Prigione S, Prescott E, et al. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J. 2016;37:24–34.
    1. Mosca L, Barrett-Connor E, Wenger NK. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation. 2011;124:2145–2154.
    1. Harris MI. Noninsulin-dependent diabetes mellitus in black and white Americans. Diabetes Metab Rev. 1990;6:71–90.
    1. Assari S, Lankarani MM, Burgard S. Black-white difference in long-term predictive power of self-rated health on all-cause mortality in United States. Ann Epidemiol. 2016;26:106–114.
    1. Assari S, Lankarani MM, Piette JD, Aikens JE. Self-rated health and glycemic control in type 2 diabetes: race by gender differences. J Racial Ethn Health Disparities. 2018;5:721–727.
    1. Kanchi R, Perlman SE, Chernov C, et al. Gender and race disparities in cardiovascular disease risk factors among New York City adults: New York City Health and Nutrition Examination Survey (NYC HANES) 2013–2014. J Urban Health. 2018;95:801–812.
    1. Regitz-Zagrosek V, Seeland U. In: Handbook of experimental pharmacology. Regitz-Zagrosek V, Seeland U, editors. Springer; Heidelberg: 2012. Sex and gender differences in clinical medicine; pp. 3–22. Berlin Heidelberg.
    1. Heron M. Deaths: leading causes for 2017. Natl Vital Stat Rep. 2019;68:1–77.
    1. WHO World health statistics 2019: monitoring health for the SDGs. 2019.
    1. Snyder ML, Love S-A, Sorlie PD, et al. Redistribution of heart failure as the cause of death: the Atherosclerosis Risk in Communities Study. Popul Health Metr. 2014;12:10.
    1. Millett ERC, Peters SAE, Woodward M. Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. BMJ. 2018;363
    1. Mehta LS, Beckie TM, DeVon HA, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation. 2016;133:916–947.
    1. Honigberg MC, Zekavat SM, Aragam K, et al. Association of premature natural and surgical menopause with incident cardiovascular disease. JAMA. 2019;322
    1. Bugiardini R, Ricci B, Cenko E, et al. Delayed care and mortality among women and men with myocardial infarction. J Am Heart Assoc. 2017;6
    1. Dreyer RP, Beltrame JF, Tavella R, et al. Evaluation of gender differences in door-to-balloon time in ST-elevation myocardial infarction. Heart Lung Circ. 2013;22:861–869.
    1. Mahmoud KD, Gu YL, Nijsten MW, et al. Interhospital transfer due to failed prehospital diagnosis for primary percutaneous coronary intervention: an observational study on incidence, predictors, and clinical impact. Eur Heart J Acute Cardiovasc Care. 2013;2:166–175.
    1. Melberg T, Kindervaag B, Rosland J. Gender-specific ambulance priority and delays to primary percutaneous coronary intervention: a consequence of the patients' presentation or the management at the emergency medical communications center? Am Heart J. 2013;166:839–845.
    1. D'Onofrio G, Safdar B, Lichtman JH, et al. Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study. Circulation. 2015;131:1324–1332.
    1. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001;141:735–741.
    1. Bairey Merz CN, Pepine CJ, Walsh MN, et al. Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade. Circulation. 2017;135:1075–1092.
    1. Greenwood BN, Carnahan S, Huang L. Patient-physician gender concordance and increased mortality among female heart attack patients. Proc Natl Acad Sci USA. 2018;115:8569–8574.
    1. Pelletier R, Khan NA, Cox J, et al. Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young? J Am Coll Cardiol. 2016;67:127–135.
    1. Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov. 2006;5:425–438.
    1. Regitz-Zagrosek V, Oertelt-Prigione S, Prescott E, et al. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J. 2016;37:24–34.
    1. Petrov G, Dworatzek E, Schulze TM, et al. Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. JACC Cardiovasc Imaging. 2014;7:1073–1080.
    1. Petrov G, Regitz-Zagrosek V, Lehmkuhl E, et al. Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Circulation. 2010;122(suppl):S23–S28.
    1. Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev. 2017;97:1–37.
    1. Barcena de Arellano ML, Pozdniakova S, Kühl AA, Baczko I, Ladilov Y, Regitz-Zagrosek V. Sex differences in the aging human heart: decreased sirtuins, pro-inflammatory shift and reduced anti-oxidative defense. Aging (Albany NY) 2019;11:1918–1933.
    1. Roswell RO, Kunkes J, Chen AY, et al. Impact of sex and contact-to-device time on clinical outcomes in acute ST-segment elevation myocardial infarction—findings from the national cardiovascular data registry. J Am Heart Assoc. 2017;6
    1. Wei J, Mehta PK, Grey E, et al. Sex-based differences in quality of care and outcomes in a health system using a standardized STEMI protocol. Am Heart J. 2017;191:30–36.
    1. Santema BT, Ouwerkerk W, Tromp J, et al. Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study. Lancet. 2019;394:1254–1263.
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.
    1. Wagner AD, Oertelt-Prigione S, Adjei A, et al. Gender medicine and oncology: report and consensus of an ESMO workshop. Ann Oncol. 2019;30:1912–1924.
    1. McCartney G, Mahmood L, Leyland AH, Batty GD, Hunt K. Contribution of smoking-related and alcohol-related deaths to the gender gap in mortality: evidence from 30 European countries. Tob Control. 2011;20:166–168.
    1. Clocchiatti A, Cora E, Zhang Y, Dotto GP. Sexual dimorphism in cancer. Nat Rev Cancer. 2016;16:330–339.
    1. Williams LA, Richardson M, Marcotte EL, Poynter JN, Spector LG. Sex ratio among childhood cancers by single year of age. Pediatr Blood Cancer. 2019;66
    1. Dunford A, Weinstock DM, Savova V, et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat Genet. 2017;49:10–16.
    1. Chua HH, Tsuei DJ, Lee PH, et al. RBMY, a novel inhibitor of glycogen synthase kinase 3β, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma. Hepatology. 2015;62:1480–1496.
    1. Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55:570–578.
    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
    1. Gardner DK, Larman MG, Thouas GA. Sex-related physiology of the preimplantation embryo. Mol Hum Reprod. 2010;16:539–547.
    1. Rubin JB, Lagas JS, Broestl L, Sponagel J, et al. Sex differences in cancer mechanisms. Biol Sex Differ. 2020;11:17.
    1. Sun T, Warrington NM, Luo J, et al. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J Clin Invest. 2014;124:4123–4133.
    1. Li Y, Xu A, Jia S, Huang J. Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma. Oncol Lett. 2019;17:4222–4228.
    1. Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H. Comparison of 17 641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57–64.
    1. Sun Y, Mironova V, Chen Y, et al. Molecular pathway analysis indicates a distinct metabolic phenotype in women with right-sided colon cancer. Transl Oncol. 2020;13:42–56.
    1. Conforti F, Pala L, Bagnardi V, et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19:737–746.
    1. Yang W, Warrington NM, Taylor SJ, et al. Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Sci Transl Med. 2019;11
    1. Lopes-Ramos CM, Kuijjer ML, Ogino S, et al. Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism. Cancer Res. 2018;78:5538–5547.
    1. Ippolito JE, Yim AK, Luo J, Chinnaiyan P, Rubin JB. Sexual dimorphism in glioma glycolysis underlies sex differences in survival. JCI Insight. 2017;2
    1. Delbridge ARD, Kueh AJ, Ke F, et al. Loss of p53 causes stochastic aberrant X-chromosome inactivation and female-specific neural tube defects. Cell Rep. 2019;27:442–454.
    1. Syamlal G, Doney B, Mazurek JM. Chronic obstructive pulmonary disease prevalence among adults who have never smoked, by industry and occupation—United States, 2013–2017. MMWR Morb Mortal Wkly Rep. 2019;68:303–307.
    1. Hardin M, Foreman M, Dransfield MT, et al. Sex-specific features of emphysema among current and former smokers with COPD. Eur Respir J. 2016;47:104–112.
    1. DeMeo DL, Ramagopalan S, Kavati A, et al. Women manifest more severe COPD symptoms across the life course. Int J Chron Obstruct Pulmon Dis. 2018;13:3021–3029.
    1. Foreman MG, Zhang L, Murphy J, et al. Early-onset chronic obstructive pulmonary disease is associated with female sex, maternal factors, and African American race in the COPDGene Study. Am J Respir Crit Care Med. 2011;184:414–420.
    1. Pinkerton KE, Harbaugh M, Han MK, et al. Women and lung disease. Sex differences and global health disparities. Am J Respir Crit Care Med. 2015;192:11–16.
    1. Stolz D, Kostikas K, Loefroth E, et al. Differences in COPD exacerbation risk between women and men: analysis from the UK Clinical Practice Research Datalink data. Chest. 2019;156:674–684.
    1. Shah R, Newcomb DC. Sex bias in asthma prevalence and pathogenesis. Front Immunol. 2018;9
    1. Zein JG, Denson JL, Wechsler ME. Asthma over the adult life course: gender and hormonal influences. Clin Chest Med. 2019;40:149–161.
    1. Sánchez-Ramos JL, Pereira-Vega AR, Alvarado-Gómez F, Maldonado-Pérez JA, Svanes C, Gómez-Real F. Risk factors for premenstrual asthma: a systematic review and meta-analysis. Expert Rev Respir Med. 2017;11:57–72.
    1. Redmond AM, James AW, Nolan SH, Self TH. Premenstrual asthma: emphasis on drug therapy options. J Asthma. 2004;41:687–693.
    1. Robijn AL, Murphy VE, Gibson PG. Recent developments in asthma in pregnancy. Curr Opin Pulm Med. 2019;25:11–17.
    1. Li X, Obeidat M, Zhou G, et al. Responsiveness to ipratropium bromide in male and female patients with mild to moderate chronic obstructive pulmonary disease. EBioMedicine. 2017;19:139–145.
    1. Tsiligianni I, Mezzi K, Fucile S, et al. Response to indacaterol/glycopyrronium (ind/gly) by sex in patients with COPD: a pooled analysis from the IGNITE Program. COPD. 2017;14:375–381.
    1. Zemp E, Schikowski T, Dratva J, Schindler C, Probst-Hensch N. Asthma and the menopause: a systematic review and meta-analysis. Maturitas. 2012;73:212–217.
    1. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139:e56–e528.
    1. Howe MD, McCullough LD. Prevention and management of stroke in women. Expert Rev Cardiovasc Ther. 2015;13:403–415.
    1. Reeves MJ, Bushnell CD, Howard G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7:915–926.
    1. Sundström J, Söderholm M, Söderberg S, et al. Risk factors for subarachnoid haemorrhage: a nationwide cohort of 950 000 adults. Int J Epidemiol. 2019;48:2018–2025.
    1. Woo D, James ML. Sex differences exist after intracerebral hemorrhage but may not affect outcome. Neurology. 2016;87:244.
    1. Cordonnier C, Sprigg N, Sandset EC, et al. Stroke in women—from evidence to inequalities. Nat Rev Neurol. 2017;13:521–532.
    1. Appelros P, Nydevik I, Viitanen M. Poor outcome after first-ever stroke: predictors for death, dependency, and recurrent stroke within the first year. Stroke. 2003;34:122–126.
    1. Bots SH, Peters SAE, Woodward M. Sex differences in coronary heart disease and stroke mortality: a global assessment of the effect of ageing between 1980 and 2010. BMJ Glob Health. 2017;2
    1. Towfighi A, Saver JL, Engelhardt R, Ovbiagele B. A midlife stroke surge among women in the United States. Neurology. 2007;69:1898–1904.
    1. McCullough LD, Alkayed NJ, Traystman RJ, Williams MJ, Hurn PD. Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke. Stroke. 2001;32:796–802.
    1. Bokslag A, Teunissen PW, Franssen C, et al. Effect of early-onset preeclampsia on cardiovascular risk in the fifth decade of life. Am J Obstet Gynecol. 2017;216:523.e1–523.e7.
    1. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:1545–1588.
    1. Blackburn P, Després J-P, Lamarche B, et al. Postprandial variations of plasma inflammatory markers in abdominally obese men. Obesity (Silver Spring) 2006;14:1747–1754.
    1. Carrasquilla GD, Frumento P, Berglund A, et al. Postmenopausal hormone therapy and risk of stroke: a pooled analysis of data from population-based cohort studies. PLoS Med. 2017;14
    1. O'Donnell MJ, Chin SL, Rangarajan S, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016;388:761–775.
    1. Lisabeth LD, Reeves MJ, Baek J, et al. Factors influencing sex differences in poststroke functional outcome. Stroke. 2015;46:860–863.
    1. Phan HT, Blizzard CL, Reeves MJ, et al. Sex differences in long-term quality of life among survivors after stroke in the INSTRUCT. Stroke. 2019;50:2299–2306.
    1. Caso V, Santalucia P, Acciarresi M, Pezzella FR, Paciaroni M. Antiplatelet treatment in primary and secondary stroke prevention in women. Eur J Intern Med. 2012;23:580–585.
    1. Fraticelli L, Freyssenge J, Claustre C, et al. Sex-related differences in management and outcome of acute ischemic stroke in eligible patients to thrombolysis. Cerebrovasc Dis. 2019;47:196–204.
    1. Sheth SA, Lee S, Warach SJ, et al. Sex differences in outcome after endovascular stroke therapy for acute ischemic stroke. Stroke. 2019;50:2420–2427.
    1. Ferretti MT, Iulita MF, Cavedo E, et al. Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol. 2018;14:457–469.
    1. Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer's disease: a call to action. Alzheimers Dement. 2018;14:1171–1183.
    1. Alzheimer's Association 2019 Alzheimer's disease facts and figures. Alzheimers Dement. 2019;15:321–387.
    1. Neu SC, Pa J, Kukull W, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 2017;74:1178–1189.
    1. Riedel BC, Thompson PM, Brinton RD. Age, APOE and sex: triad of risk of Alzheimer's disease. J Steroid Biochem Mol Biol. 2016;160:134–147.
    1. Altmann A, Tian L, Henderson VW, Greicius MD. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014;75:563–573.
    1. Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol. 2018;75:989–998.
    1. Buckley RF, Mormino EC, Rabin JS, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol. 2019;76:542–551.
    1. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015;11:393–405.
    1. Mosconi L, Berti V, Quinn C, et al. Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery. PLoS One. 2017;12
    1. Sundermann EE, Maki P, Biegon A, et al. Sex-specific norms for verbal memory tests may improve diagnostic accuracy of amnestic MCI. Neurology. 2019;93:e1881–e1889.
    1. Sundermann EE, Biegon A, Rubin LH, Lipton RB, Landau S, Maki PM. Does the female advantage in verbal memory contribute to underestimating Alzheimer's disease pathology in women versus men? J Alzheimers Dis. 2017;56:947–957.
    1. Ma M, Dorstyn D, Ward L, Prentice S. Alzheimers' disease and caregiving: a meta-analytic review comparing the mental health of primary carers to controls. Aging Ment Health. 2018;22:1395–1405.
    1. Canevelli M, Quarata F, Remiddi F, et al. Sex and gender differences in the treatment of Alzheimer's disease: a systematic review of randomized controlled trials. Pharmacol Res. 2017;115:218–223.
    1. Giacobini E, Pepeu G. Sex and gender differences in the brain cholinergic system and in the response to therapy of Alzheimer disease with cholinesterase inhibitors. Curr Alzheimer Res. 2018;15:1077–1084.
    1. Zhu L, Rochon PA, Gruneir A, et al. Sex differences in the prevalent use of oral formulations of cholinesterase inhibitors in older adults with dementia. Drugs Aging. 2019;36:875–884.
    1. Huebschmann AG, Huxley RR, Kohrt WM, Zeitler P, Regensteiner JG, Reusch JEB. Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course. Diabetologia. 2019;62:1761–1772.
    1. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med. 2006;144:350–357.
    1. Mauvais-Jarvis F. Gender differences in glucose homeostasis and diabetes. Physiol Behav. 2018;187:20–23.
    1. Kautzky-Willer A, Harreiter J, Pacini G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocr Rev. 2016;37:278–316.
    1. Mauvais-Jarvis F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab. 2011;22:24–33.
    1. Mauvais-Jarvis F, Manson JE, Stevenson JC, Fonseca VA. Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms and clinical implications. Endocr Rev. 2017;38:173–188.
    1. Yassin A, Haider A, Haider KS, et al. Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry Study. Diabetes Care. 2019;42:1104–1111.
    1. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139:e56–e528.
    1. Regensteiner JG, Golden S, Huebschmann AG, et al. Sex differences in the cardiovascular consequences of diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2015;132:2424–2447.
    1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–952.
    1. Peters SA, Huxley RR, Woodward M. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858 507 individuals and 28 203 coronary events. Diabetologia. 2014;57:1542–1551.
    1. Peters SA, Huxley RR, Sattar N, Woodward M. Sex differences in the excess risk of cardiovascular diseases associated with type 2 diabetes: potential explanations and clinical implications. Curr Cardiovasc Risk Rep. 2015;9:36.
    1. Wannamethee SG, Papacosta O, Lawlor DA, et al. Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women's Heart Health Study. Diabetologia. 2012;55:80–87.
    1. Du T, Fernandez C, Barshop R, et al. Sex differences in cardiovascular risk profile from childhood to midlife between individuals who did and did not develop diabetes at follow-up: the Bogalusa Heart Study. Diabetes Care. 2019;42:635–643.
    1. Gouni-Berthold I, Berthold HK, Mantzoros CS, Böhm M, Krone W. Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes. Diabetes Care. 2008;31:1389–1391.
    1. de Ritter R, de Jong M, Vos RC, et al. Sex differences in the risk of vascular disease associated with diabetes. Biol Sex Differ. 2020;11:1.
    1. Ohkuma T, Komorita Y, Peters SAE, Woodward M. Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals. Diabetologia. 2019;62:1550–1560.
    1. Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med. 2007;147:149–155.
    1. Dennis JM, Henley WE, Weedon MN, et al. Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: a framework for evaluating stratification using routine clinical and individual trial data. Diabetes Care. 2018;41:1844–1853.
    1. Krammer F, Smith GJD, Fouchier RAM, et al. Influenza. Nat Rev Dis Primers. 2018;4:3.
    1. Morgan R, Klein SL. The intersection of sex and gender in the treatment of influenza. Curr Opin Virol. 2019;35:35–41.
    1. Vermillion MS, Ursin RL, Kuok DIT, et al. Production of amphiregulin and recovery from influenza is greater in males than females. Biol Sex Differ. 2018;9:24.
    1. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009;374:451–458.
    1. Vom Steeg LG, Vermillion MS, Hall OJ, et al. Age and testosterone mediate influenza pathogenesis in male mice. Am J Physiol Lung Cell Mol Physiol. 2016;311:L1234–L1244.
    1. Klein SL, Pekosz A, Passaretti C, Anker M, Olukoya P. World Health Organization; Geneva: 2010. Sex, gender and influenza.
    1. Casimir GJ, Lefèvre N, Corazza F, Duchateau J. Sex and inflammation in respiratory diseases: a clinical viewpoint. Biol Sex Differ. 2013;4:16.
    1. Migeon BR. The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. JAMA. 2006;295:1428–1433.
    1. Borchgrevink CP, Cha J, Kim S. Hand washing practices in a college town environment. J Environ Health. 2013;75:18–24.
    1. van de Mortel T, Bourke R, McLoughlin J, Nonu M, Reis M. Gender influences handwashing rates in the critical care unit. Am J Infect Control. 2001;29:395–399.
    1. Potluri T, Fink AL, Sylvia KE, et al. Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females. NPJ Vaccines. 2019;4:29.
    1. Engler RJ, Nelson MR, Klote MM, et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses. Arch Intern Med. 2008;168:2405–2414.
    1. Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep. 2005;54:1–40.
    1. Fink AL, Engle K, Ursin RL, Tang WY, Klein SL. Biological sex affects vaccine efficacy and protection against influenza in mice. Proc Natl Acad Sci USA. 2018;115:12477–12482.
    1. Roth GA, Abate D, Abate KH, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788.
    1. Inker LA, Shafi T, Okparavero A, et al. Effects of race and sex on measured GFR: the multi-ethnic study of atherosclerosis. Am J Kidney Dis. 2016;68:743–751.
    1. Carrero JJ, Hecking M, Chesnaye NC, Jager KJ. Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat Rev Nephrol. 2018;14:151–164.
    1. Covella B, Vinturache AE, Cabiddu G, et al. A systematic review and meta-analysis indicates long-term risk of chronic and end-stage kidney disease after preeclampsia. Kidney Int. 2019;96:711–727.
    1. Valdivielso JM, Jacobs-Cachá C, Soler MJ. Sex hormones and their influence on chronic kidney disease. Curr Opin Nephrol Hypertens. 2019;28:1–9.
    1. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol. 2005;16:180–188.
    1. Gasparini A, Evans M, Coresh J, et al. Prevalence and recognition of chronic kidney disease in Stockholm healthcare. Nephrol Dial Transplant. 2016;31:2086–2094.
    1. Kausz AT, Obrador GT, Arora P, Ruthazer R, Levey AS, Pereira BJ. Late initiation of dialysis among women and ethnic minorities in the United States. J Am Soc Nephrol. 2000;11:2351–2357.
    1. Hecking M, Bieber BA, Ethier J, et al. Sex-specific differences in hemodialysis prevalence and practices and the male-to-female mortality rate: the Dialysis Outcomes and Practice Patterns Study (DOPPS) PLoS Med. 2014;11
    1. Morton RL, Turner RM, Howard K, Snelling P, Webster AC. Patients who plan for conservative care rather than dialysis: a national observational study in Australia. Am J Kidney Dis. 2012;59:419–427.
    1. Markell M, Brar A, Stefanov DG, Salifu MO. Gender disparity in fistula use at initiation of hemodialysis varies markedly across ESRD networks—analysis of USRDS data. Hemodial Int. 2018;22:168–175.
    1. Caplin N, Sedlacek M, Teodorescu V, Falk A, Uribarri J. Venous access: women are equal. Am J Kidney Dis. 2003;41:429–432.
    1. Duncan JA, Levin A. Sex, haemoglobin and kidney disease: new perspectives. Eur J Clin Invest. 2005;35(suppl 3):52–57.
    1. Spalding EM, Chandna SM, Davenport A, Farrington K. Kt/V underestimates the hemodialysis dose in women and small men. Kidney Int. 2008;74:348–355.
    1. Guy J, Peters MG. Liver disease in women: the influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol Hepatol (N Y) 2013;9:633–639.
    1. Shimizu I, Kamochi M, Yoshikawa H, Nakayama Y. InTech; London: 2012. Gender difference in alcoholic liver disease trends in alcoholic liver disease research—clinical and scientific aspects.
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.
    1. Lonardo A, Nascimbeni F, Ballestri S, et al. Sex differences in NAFLD: state of the art and identification of research gaps. Hepatology. 2019;70:1457–1469.
    1. Lonardo A, Nascimbeni F, Targher G, et al. AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions. Dig Liver Dis. 2017;49:471–483.
    1. Florio AA, Graubard BI, Yang B, et al. Oophorectomy and risk of non-alcoholic fatty liver disease and primary liver cancer in the Clinical Practice Research Datalink. Eur J Epidemiol. 2019;34:871–878.
    1. Lonardo A, Mantovani A, Lugari S, Targher G. NAFLD in some common endocrine diseases: prevalence, pathophysiology, and principles of diagnosis and management. Int J Mol Sci. 2019;20
    1. Varì R, Scazzocchio B, D'Amore A, Giovannini C, Gessani S, Masella R. Gender-related differences in lifestyle may affect health status. Ann Ist Super Sanita. 2016;52:158–166.
    1. Friedrich MJ. Depression is the leading cause of disability around the world. JAMA. 2017;317
    1. Marcus SM, Kerber KB, Rush AJ, et al. Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study. Compr Psychiatry. 2008;49:238–246.
    1. Call JB, Shafer K. Gendered manifestations of depression and help seeking among men. Am J Men Health. 2018;12:41–51.
    1. Nolen-Hoeksema S. Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol. 2012;8:161–187.
    1. GBD 2015 Mortality and Causes of Death Collaborators Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544.
    1. Weissman MM, Bland RC, Canino GJ, et al. Prevalence of suicide ideation and suicide attempts in nine countries. Psychol Med. 1999;29:9–17.
    1. Bale TL, Epperson CN. Sex differences and stress across the lifespan. Nat Neurosci. 2015;18:1413–1420.
    1. Shanmugan S, Epperson CN. Estrogen and the prefrontal cortex: towards a new understanding of estrogen's effects on executive functions in the menopause transition. Hum Brain Mapp. 2014;35:847–865.
    1. Epperson CN, Sammel MD, Bale TL, et al. Adverse childhood experiences and risk for first-episode major depression during the menopause transition. J Clin Psychiatry. 2017;78:e298–e307.
    1. Viktorin A, Meltzer-Brody S, Kuja-Halkola R, et al. Heritability of perinatal depression and genetic overlap with nonperinatal depression. Am J Psychiatry. 2016;173:158–165.
    1. Kendler KS, Thornton LM, Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry. 2001;158:587–593.
    1. LeGates TA, Kvarta MD, Thompson SM. Sex differences in antidepressant efficacy. Neuropsychopharmacology. 2019;44:140–154.
    1. Sramek JJ, Murphy MF, Cutler NR. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin Neurosci. 2016;18:447–457.
    1. Labonté B, Engmann O, Purushothaman I, et al. Sex-specific transcriptional signatures in human depression. Nat Med. 2017;23:1102–1111.
    1. European Commissionç The state of men's health in Europe. 2011.
    1. Cummings SR, Cawthon PM, Ensrud KE, et al. BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women. J Bone Miner Res. 2006;21:1550–1556.
    1. Francis MD, Valent DJ. Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. J Musculoskelet Neuronal Interact. 2007;7:2–8.
    1. Werling DM, Geschwind DH. Sex differences in autism spectrum disorders. Curr Opin Neurol. 2013;26:146–153.
    1. Jurado-Coronel JC, Cabezas R, Ávila Rodríguez MF, Echeverria V, García-Segura LM, Barreto GE. Sex differences in Parkinson's disease: features on clinical symptoms, treatment outcome, sexual hormones and genetics. Front Neuroendocrinol. 2018;50:18–30.
    1. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2:777–780.
    1. Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol. 2017;16:76–87.
    1. Smink FRE, van Hoeken D, Oldehinkel AJ, Hoek HW. Prevalence and severity of DSM-5 eating disorders in a community cohort of adolescents. Int J Eat Disord. 2014;47:610–619.
    1. Marina S, Piemonti L. Gender and age effects on the rates of infection and deaths in individuals with confirmed SARS-CoV-2 infection in six European countries. Lancet (in press).
    1. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
    1. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323:1574–1581.
    1. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323
    1. Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol. 2017;198:4046–4053.
    1. Bairey Merz CN, Andersen H, Sprague E, et al. Knowledge, attitudes, and beliefs regarding cardiovascular disease in women: the women's heart alliance. J Am Coll Cardiol. 2017;70:123–132.
    1. Melloni C, Berger JS, Wang TY, et al. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135–142.
    1. Tannenbaum C, Ellis RP, Eyssel F, Zou J, Schiebinger L. Sex and gender analysis improves science and engineering. Nature. 2019;575:137–146.
    1. Chin EL, Hoggatt M, McGregor AJ, et al. Sex and Gender Medical Education Summit: a roadmap for curricular innovation. Biol Sex Differ. 2016;7:52.

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