The role of sex and pregnancy in multiple sclerosis: what do we know and what should we do?

References

• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–286.
   PubMed Web of Science ®Google Scholar
• Hammond SR, de Wytt C, Maxwell IC, et al. The epidemiology of multiple sclerosis in Queensland, Australia. J Neurol Sci. 1987;80:185–204.
   PubMed Web of Science ®Google Scholar
• Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. clinical course and disability. Brain. 1989;112:133–146.
   PubMed Web of Science ®Google Scholar
• Ahlgren C, Odén A, Lycke J. High nationwide prevalence of multiple sclerosis in Sweden. Mult Scler. 2011;17:901–908.
   PubMed Web of Science ®Google Scholar
• Wallin MT, Culpepper WJ, Coffman P, et al. The gulf war era multiple sclerosis cohort: age and incidence rates by race, sex and service. Brain. 2012;135:1778–1785.
   PubMed Web of Science ®Google Scholar
• Kampman MT, Aarseth JH, Grytten N, et al. Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to Latitude in Norway. J Neurol. 2013;260:1481–1488.
   PubMedGoogle Scholar
• Westerlind H, Boström I, Stawiarz L, et al. New data identify an increasing sex ratio of multiple sclerosis in Sweden. Mult Scler. 2014;20:1578–1583.
   PubMed Web of Science ®Google Scholar
• Miclea A, Salmen A, Zoehner G, et al. Age-dependent variation of female preponderance across different phenotypes of multiple sclerosis: a retrospective cross-sectional study. CNS Neurosci Ther. 2019;25:527–531.
   PubMed Web of Science ®Google Scholar
• Alonso A, Jick SS, Olek MJ, et al. Incidence of multiple sclerosis in the United Kingdom: findings from a population-based cohort. J Neurol. 2007;254:1736–1741.
   PubMed Web of Science ®Google Scholar
• Yaouanq J, Tron I, Kerbrat A, et al. Register-based incidence of multiple sclerosis in Brittany (North-Western France), 2000-2001. Acta Neurol Scand. 2015;131:321–328.
   PubMed Web of Science ®Google Scholar
• Akhtar S, Alroughani R, Ahmed SF, et al. Retrospective cohort study of gender differential in risk of multiple sclerosis in Kuwait. Neuroepidemiology. 2016;46:203–208.
   PubMed Web of Science ®Google Scholar
• O’Connell K, Tubridy N, Hutchinson M, et al. Incidence of multiple sclerosis in the Republic of Ireland: a prospective population-based study. Mult Scler Relat Disord. 2017;13:75–80.
   PubMed Web of Science ®Google Scholar
• Cheraghmakani H, Baghbanian SM, HabibiSaravi R, et al. Age and sex-adjusted incidence and yearly prevalence of multiple sclerosis (Ms) in Mazandaran Province, Iran: an 11-years study. PloS one. 2020;15:e0235562.
   PubMed Web of Science ®Google Scholar
• Optic Neuritis Study Group. The 5-year risk of Ms after optic neuritis. Experience of the optic neuritis treatment trial. Optic neuritis study group. Neurology. 1997;49:1404–1413.
   PubMed Web of Science ®Google Scholar
• Swanton JK, Fernando KT, Dalton CM, et al. Early MRI in optic neuritis: the risk for clinically definite multiple sclerosis. Mult Scler. 2010;16:156–165.
   PubMed Web of Science ®Google Scholar
• Kinnunen E. the incidence of optic neuritis and its prognosis for multiple sclerosis. Acta Neurol Scand. 1983;68:371–377.
   PubMed Web of Science ®Google Scholar
• Liu Y, Duan Y, Yu C, et al. Clinical Isolated Syndrome: a 3-year follow-up study in China. Clin Neurol Neurosurg. 2011;113:658–660.
   PubMed Web of Science ®Google Scholar
• Sandberg-Wollheim M. Optic neuritis: studies on the cerebrospinal fluid in relation to clinical course in 61 patients. Acta Neurol Scand. 1975;52:167–178.
   PubMed Web of Science ®Google Scholar
• Cohen MM, Lessell S, Wolf PA. A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis. Neurology. 1979;29:208–213.
   PubMed Web of Science ®Google Scholar
• Landy PJ. a prospective study of the risk of developing multiple sclerosis in optic neuritis in a tropical and sub-tropical area. J Neurol Neurosurg Psychiatry. 1983;46:659–661.
   PubMed Web of Science ®Google Scholar
• Rizzo JF 3rd, Lessell S. Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long-term prospective study. Neurology. 1988;38:185–190.
   PubMed Web of Science ®Google Scholar
• Bentzen J, Flachs EM, Stenager E, et al. Prevalence of multiple sclerosis in Denmark 1950–2005. Mult Scler. 2010;16:520–525.
   PubMedGoogle Scholar
• Orton SM, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a Longitudinal study. Lancet Neurol. 2006;5:932–936.
   PubMed Web of Science ®Google Scholar
• Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71:129–135.
   PubMed Web of Science ®Google Scholar
• Celius EG, Harbo HF, Egeland T, et al. Sex and age at diagnosis are correlated with the Hla-Dr2, Dq6 Haplotype in multiple sclerosis. J Neurol Sci. 2000;178:132–135.
   PubMed Web of Science ®Google Scholar
• Hirst CL, Ingram G, Pickersgill TP, et al. Increasing prevalence and incidence of multiple sclerosis in south east wales. J Neurol Neurosurg Psychiatry. 2008;80:386–391.
   PubMed Web of Science ®Google Scholar
• Osoegawa M, Kira J, Fukazawa T, et al. Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: nationwide survey results over 30 years. Mult Scler. 2008;15:159–173.
   PubMed Web of Science ®Google Scholar
• Sadovnick AD. European Charcot foundation lecture: the natural history of multiple sclerosis and gender. J Neurol Sci. 2009;286:1–5.
   PubMed Web of Science ®Google Scholar
• Koch-Henriksen N, Sørensen PS. the changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9:520–532.
   PubMed Web of Science ®Google Scholar
• Sadovnick AD, Yee IM, Criscuoli M, et al. Genes and environment in multiple sclerosis: impact of temporal changes in the sex ratio on recurrence risks. Mult Scler. 2022;28(3) :359–368.
   PubMed Web of Science ®Google Scholar
• Taylor BV, Lucas RM, Dear K, et al. Latitudinal variation in incidence and type of first central nervous system demyelinating events. Mult Scler. 2010;16:398–405.
   PubMed Web of Science ®Google Scholar
• Trojano M, Lucchese G, Graziano G, et al. Geographical variations in sex ratio trends over time in multiple sclerosis. PloS one. 2012;7:e48078.
   PubMed Web of Science ®Google Scholar
• Wang CX, Greenberg BM. Pediatric multiple sclerosis: from recognition to practical clinical management. Neurol Clin. 2018;36:135–149.
   PubMed Web of Science ®Google Scholar
• Cottrell DA, Kremenchutzky M, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. 5. the clinical features and natural history of primary progressive multiple sclerosis. Brain. 1999;122(Pt 4):625–639.
   PubMed Web of Science ®Google Scholar
• Stevenson VL, Miller DH, Rovaris M, et al. Primary and transitional progressive ms: a clinical and MRI cross-sectional study. Neurology. 1999;52:839–845.
   PubMed Web of Science ®Google Scholar
• Blinkenberg M, Kjellberg J, Ibsen R, et al. Increased socioeconomic burden in patients with primary progressive multiple sclerosis: a Danish nationwide population-based study. Mult Scler Relat Disord. 2020;46:102567.
   PubMed Web of Science ®Google Scholar
• Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136:3609–3617.
   PubMed Web of Science ®Google Scholar
• Brola W, Sobolewski P, Żak M, et al. Profile of polish patients with primary progressive multiple sclerosis. Mult Scler Relat Disord. 2019;33:33–38.
   PubMed Web of Science ®Google Scholar
• Souissi A, Mrabet S, Nasri A, et al. Clinical predictors of disease progression in a cohort of Tunisian progressive multiple sclerosis. Mult Scler Relat Disord. 2021;56:103232.
   PubMed Web of Science ®Google Scholar
• Luetic GG, Menichini ML, Vrech C, et al. Clinical and demographic characteristics of male Ms patients included in the national registry-relevarem. Does sex or phenotype make the difference in the association with poor prognosis? Mult Scler Relat Disord. 2022;58:103401.
   PubMedGoogle Scholar
• Engelhard J, Oleske DM, Schmitting S, et al. Multiple sclerosis by phenotype in Germany. Mult Scler Relat Disord. 2022;57:103326.
   PubMedGoogle Scholar
• Lassmann H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol. 2018;9:3116.
   PubMed Web of Science ®Google Scholar
• Antel J, Antel S, Caramanos Z, et al. Primary progressive multiple sclerosis: part of the Ms disease spectrum or separate disease entity? Acta Neuropathol. 2012;123:627–638.
   PubMed Web of Science ®Google Scholar
• Ontaneda D. Progressive multiple sclerosis. Continuum (Minneap Minn). 2019;25:736–752.
   PubMedGoogle Scholar
• Leibowitz U, Alter M. Clinical factors associated with increased disability in multiple sclerosis. Acta Neurol Scand. 1970;46:53–70.
   PubMed Web of Science ®Google Scholar
• Abuawad M, Ziyadeh-Isleem A, Alkaiyat A, et al. Epidemiology of multiple sclerosis in west bank of Palestine. Mult Scler Relat Disord. 2022;59:103686.
   PubMedGoogle Scholar
• Rommer PS, Ellenberger D, Hellwig K, et al. Relapsing and progressive Ms: the sex-specific perspective. Ther Adv Neurol Disord. 2020;13:1756286420956495.
   Web of Science ®Google Scholar
• Wikström J, Poser S, Ritter G. Optic neuritis as an initial symptom in multiple sclerosis. Acta Neurol Scand. 1980;61:178–185.
   PubMed Web of Science ®Google Scholar
• Ribbons KA, McElduff P, Boz C, et al. Male sex is independently associated with faster disability accumulation in relapse-onset ms but not in primary progressive Ms. PloS one. 2015;10:e0122686.
   PubMed Web of Science ®Google Scholar
• Wilkins A. Cerebellar dysfunction in multiple sclerosis. Front Neurol. 2017;8:312.
   PubMed Web of Science ®Google Scholar
• Kalincik T, Buzzard K, Jokubaitis V, et al. Risk of relapse phenotype recurrence in multiple sclerosis. Mult Scler. 2014;20:1511–1522.
   PubMed Web of Science ®Google Scholar
• Held U, Heigenhauser L, Shang C, et al. Predictors of relapse rate in Ms clinical trials. Neurology. 2005;65:1769–1773.
   PubMed Web of Science ®Google Scholar
• Magyari M, Koch-Henriksen N, Laursen B, et al. Gender effects on treatment response to interferon-beta in multiple sclerosis. Acta Neurol Scand. 2014;130:374–379.
   PubMed Web of Science ®Google Scholar
• Tremlett H, Zhao Y, Joseph J, et al. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79:1368–1374.
   PubMed Web of Science ®Google Scholar
• Sadovnick AD, Yee IM, Criscuoli M, et al. Genes and environment in multiple sclerosis: impact of temporal changes in the sex ratio on recurrence risks. Mult Scler. 2022;28:359–368.
   PubMed Web of Science ®Google Scholar
• Detels R, Clark VA, Valdiviezo NL, et al. Factors associated with a rapid course of multiple sclerosis. Arch Neurol. 1982;39:337–341.
   PubMed Web of Science ®Google Scholar
• Confavreux C. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126:770–782.
   PubMed Web of Science ®Google Scholar
• Leray E, Yaouanq J, Le Page E, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133:1900–1913.
   PubMed Web of Science ®Google Scholar
• Shirani A, Zhao Y, Kingwell E, et al. Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975-2009). Mult Scler. 2012;18:442–450.
   PubMed Web of Science ®Google Scholar
• Wolfson C, Confavreux C. A Markov model of the natural history of multiple sclerosis. Neuroepidemiology. 1985;4:227–239.
   PubMedGoogle Scholar
• Weinshenker BG, Rice GP, Noseworthy JH, et al. The Natural History of Multiple Sclerosis: a Geographically Based Study. 3. Multivariate Analysis of Predictive Factors and Models of Outcome. Brain. 1991;114:1045–1056.
   PubMed Web of Science ®Google Scholar
• Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain. 1993;116:117–134.
   PubMed Web of Science ®Google Scholar
• Glad S, Nyland H, Aarseth J, et al. Long-term follow-up of benign multiple sclerosis in Hordaland County, Western Norway. Mult Scler. 2009;15:942–950.
   PubMed Web of Science ®Google Scholar
• Koch M, Kingwell E, Rieckmann P, et al. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81:1039–1043.
   PubMed Web of Science ®Google Scholar
• Koutsis G, Evangelopoulos ME, Andreadou E, et al. the onset of multiple sclerosis in Greece: a single-center study of 1,034 consecutive patients. Eur Neurol. 2010;63:350–356.
   PubMed Web of Science ®Google Scholar
• Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology. 2006;66:172–177.
   PubMed Web of Science ®Google Scholar
• Confavreux C, Vukusic S. natural history of multiple sclerosis: a unifying concept. Brain. 2006;129:606–616.
   PubMed Web of Science ®Google Scholar
• Debouverie M. Gender as a prognostic factor and its impact on the incidence of multiple sclerosis in Lorraine, France. J Neurol Sci. 2009;286:14–17.
   PubMed Web of Science ®Google Scholar
• Debouverie M, Pittion-Vouyovitch S, Louis S, et al. Natural history of multiple sclerosis in a population-based cohort. Eur J Neurol. 2008;15:916–921.
   PubMed Web of Science ®Google Scholar
• Wolinsky JS, Shochat T, Weiss S, et al. Glatiramer acetate treatment in Ppms: why males appear to respond favorably. J Neurol Sci. 2009;286:92–98.
   PubMed Web of Science ®Google Scholar
• Vural A, Derle E, Sayat-Gürel G, et al. Predictors of progression in primary progressive multiple sclerosis in a large Turkish cohort. Mult Scler Relat Disord. 2020;38:101520.
   PubMed Web of Science ®Google Scholar
• Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci. 2003;206:135–137.
   PubMed Web of Science ®Google Scholar
• Bove RM, Healy B, Augustine A, et al. Effect of gender on late-onset multiple sclerosis. Mult Scler. 2012;18:1472–1479.
   PubMed Web of Science ®Google Scholar
• Bove R, Musallam A, Healy BC, et al. No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50. BMC Neurol. 2013;13(73): DOI:https://doi.org/10.1186/1471-2377-13-73.
   Google Scholar
• Otero-Romero S, Midaglia L, Carbonell-Mirabent P, et al. Menopause does not modify disability trajectories in a longitudinal cohort of women with clinically isolated syndrome and multiple sclerosis followed from disease onset. Eur J Neurol. 2022;29:1075–1081.
   PubMed Web of Science ®Google Scholar
• Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008;14:1191–1198.
   PubMed Web of Science ®Google Scholar
• Brønnum-Hansen H. Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain. 2004;127:844–850.
   PubMed Web of Science ®Google Scholar
• Leray E, Morrissey S, Yaouanq J, et al. Long-term survival of patients with multiple sclerosis in West France. Mult Scler. 2007;13:865–874.
   PubMedGoogle Scholar
• Rollot F, Fauvernier M, Uhry Z, et al. Effects of age and disease duration on excess mortality in patients with multiple sclerosis from a French Nationwide cohort. Neurology. 2021;97:e403–e13.
   PubMed Web of Science ®Google Scholar
• Sumelahti ML, Hakama M, Elovaara I, et al. Causes of death among patients with multiple sclerosis. Mult Scler. 2010;16:1437–1442.
   PubMedGoogle Scholar
• Tower J, Arbeitman M. The genetics of gender and life span. J Biol. 2009;8(38):38.
   PubMedGoogle Scholar
• Lassmann H. Multiple sclerosis pathology: evolution of pathogenetic concepts. Brain Pathol. 2005;15:217–222.
   PubMed Web of Science ®Google Scholar
• Lucchinetti CF, Parisi J, Bruck W. The pathology of multiple sclerosis. Neurol Clin. 2005;23:77–105, vi.
   PubMed Web of Science ®Google Scholar
• Mahad D, Lassmann H, Turnbull D. Review: mitochondria and disease progression in multiple sclerosis. Neuropathol Appl Neurobiol. 2008;34:577–589.
   PubMed Web of Science ®Google Scholar
• Kuhlmann T, Goldschmidt T, Antel J, et al. Gender differences in the histopathology of Ms? J Neurol Sci. 2009;286:86–92.
   PubMed Web of Science ®Google Scholar
• Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128:2705–2712.
   PubMed Web of Science ®Google Scholar
• Wegner C, Esiri MM, Chance SA, et al. neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology. 2006;67:960–967.
   PubMed Web of Science ®Google Scholar
• Luchetti S, Fransen NL, van Eden CG, et al. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 2018;135:511–528.
   PubMed Web of Science ®Google Scholar
• Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis Plaque. Ann Neurol. 2015;78:710–721.
   PubMed Web of Science ®Google Scholar
• Ganter P, Prince C, Esiri MM. Spinal cord axonal loss in multiple sclerosis: a post-mortem study. Neuropathol Appl Neurobiol. 1999;25:459–467.
   PubMed Web of Science ®Google Scholar
• Weatherby SJ, Mann CL, Davies MB, et al. A pilot study of the relationship between gadolinium-enhancing lesions, gender effect and polymorphisms of antioxidant enzymes in multiple sclerosis. J Neurol. 2000;247:467–470.
   PubMed Web of Science ®Google Scholar
• Pozzilli C, Tomassini V, Marinelli F, et al. ‘Gender Gap’ in multiple sclerosis: magnetic resonance imaging evidence. Eur J Neurol. 2003;10:95–97.
   PubMed Web of Science ®Google Scholar
• Tomassini V, Onesti, E, Mainero, c, et al. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neurosurg Psychiatry. 2005;76:272–275.
   PubMed Web of Science ®Google Scholar
• van Walderveen MA, Tas MW, Barkhof F, et al. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology. 1994;44:327–329.
   PubMed Web of Science ®Google Scholar
• Voskuhl RR, Patel K, Paul F, et al. Sex differences in brain atrophy in multiple sclerosis. Biol Sex Differ. 2020;11:49.
   PubMed Web of Science ®Google Scholar
• Fazekas F, Enzinger C, Wallner-Blazek M, et al. Gender differences in MRI studies on multiple sclerosis. Journal of the Neurological Sciences. 2009;286(1–2):28–30.
   PubMed Web of Science ®Google Scholar
• Marschallinger R, Mühlau M, Pongratz V, et al. Geostatistical analysis of white matter lesions in multiple sclerosis identifies gender differences in lesion evolution. Front Mol Neurosci. 2018;11:460.
   PubMed Web of Science ®Google Scholar
• Luchicchi A, Preziosa P, T Hart BE. “Inside-out” Vs “Outside-in” paradigms in multiple sclerosis etiopathogenesis. Front Cell Neurosci. 2021;15:666529.
   PubMed Web of Science ®Google Scholar
• Stinissen P, Raus J, Zhang J. autoimmune pathogenesis of multiple sclerosis: role of autoreactive t lymphocytes and new immunotherapeutic strategies. Crit Rev Immunol. 1997;17:33–75.
   PubMed Web of Science ®Google Scholar
• Greer JM, Pender MP. Myelin proteolipid protein: an effective autoantigen and target of autoimmunity in multiple sclerosis. J Autoimmun. 2008;31:281–287.
   PubMed Web of Science ®Google Scholar
• Greer JM, Csurhes PA, Pender MP, et al. Effect of gender on t-cell proliferative responses to myelin proteolipid protein antigens in patients with multiple sclerosis and controls. J Autoimmun. 2004;22:345–352.
   PubMed Web of Science ®Google Scholar
• Moldovan IR, Cotleur AC, Zamor N, et al. Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens. Journal of Neuroimmunology. 2008;193(1–2):161–169.
   PubMed Web of Science ®Google Scholar
• Pelfrey CM, Cotleur AC, Lee JC, et al. Sex differences in cytokine responses to myelin peptides in multiple sclerosis. J Neuroimmunol. 2002;130:211–223.
   PubMed Web of Science ®Google Scholar
• Li R, Sun X, Shu Y, et al. Sex differences in outcomes of disease-modifying treatments for multiple sclerosis: a systematic review. Mult Scler Relat Disord. 2017;12:23–28.
   PubMed Web of Science ®Google Scholar
• Trojano M, Pellegrini F, Paolicelli D, et al. Post-marketing of disease modifying drugs in multiple sclerosis: an exploratory analysis of gender effect in interferon beta treatment. J Neurol Sci. 2009;286:109–113.
   PubMed Web of Science ®Google Scholar
• Li DK, Zhao GJ, Paty DW. Randomized Controlled Trial of interferon-beta-1a in secondary progressive Ms: MRI results. Neurology. 2001;56:1505–1513.
   PubMed Web of Science ®Google Scholar
• Ferrè L, Mogavero A, Clarelli F, et al. Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis. Multiple Sclerosis. 2020;(27)9:1374–1383.
   PubMed Web of Science ®Google Scholar
• Leibowitz U, Antonovsky A, Kats R, et al. does pregnancy increase the risk of multiple sclerosis? J Neurol Neurosurg Psychiatry. 1967;30:354–357.
   PubMed Web of Science ®Google Scholar
• Villard Mackintosh L, Vessey MP. Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception. 1993;47:161–168.
   PubMed Web of Science ®Google Scholar
• Runmarker B, Andersen O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain. 1995;118:253–261.
   PubMed Web of Science ®Google Scholar
• Nielsen NM, Jorgensen KT, Stenager E, et al. Reproductive history and risk of multiple sclerosis. Epidemiology. 2011;22:546–552.
   PubMed Web of Science ®Google Scholar
• Hedström AK, Hillert J, Olsson T, et al. Reverse causality behind the association between reproductive history and ms. Mult Scler. 2014;20:406–411.
   PubMed Web of Science ®Google Scholar
• Ponsonby AL, Lucas RM, van Dm I, et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the ausimmune study. Neurology. 2012;78:867–874.
   PubMed Web of Science ®Google Scholar
• Mohammadbeigi A, Kazemitabaee M, Etemadifar M. Risk factors of early onset of ms in women in reproductive age period: survival analysis approach. Arch Womens Ment Health. 2016;19:681–686.
   PubMed Web of Science ®Google Scholar
• Adams CJ, Wu SL, Shao X, et al. Pregnancy does not modify the risk of ms in genetically susceptible women. Neurol Neuroimmunol Neuroinflamm. 2020;7:e898.
   PubMed Web of Science ®Google Scholar
• Gasperi C, Hapfelmeier A, Schneider A, et al. Association of Pregnancies with Risk of Multiple Sclerosis. Mult Scler. 2022;13524585221080542. DOI:https://doi.org/10.1177/13524585221080542.
   Google Scholar
• Tremlett H, Marrie RA. The multiple sclerosis prodrome: emerging evidence, challenges, and opportunities. Mult Scler. 2021;27:6–12.
   PubMedGoogle Scholar
• Kopp TI, Pinborg A, Glazer CH, et al. women with female infertility seeking medically assisted reproduction are not at increased risk of developing multiple sclerosis. Hum Reprod. 2022; DOI:https://doi.org/10.1093/humrep/deac041.
   Google Scholar
• Alonso A, Clark CJ. Oral contraceptives and the risk of multiple sclerosis: a review of the epidemiologic evidence. J Neurol Sci. 2009;286:73–75.
   PubMed Web of Science ®Google Scholar
• Alonso A, Jick SS, Olek MJ, et al. Recent use of oral contraceptives and the risk of multiple sclerosis. Arch Neurol. 2005;62:1362–1365.
   PubMed Web of Science ®Google Scholar
• Hernan MA, Hohol MJ, Olek MJ, et al. Oral Contraceptives and the incidence of multiple sclerosis. Neurology. 2000;55:848–854.
   PubMed Web of Science ®Google Scholar
• Simone IL, Tortorella C, Ghirelli A. Influence of pregnancy in multiple sclerosis and impact of disease-modifying therapies. Front Neurol. 2021;12:697974.
   PubMed Web of Science ®Google Scholar
• Vukusic S, Michel L, Leguy S, et al. Pregnancy with multiple sclerosis. Rev Neurol (Paris). 2021;177:180–194.
   PubMed Web of Science ®Google Scholar
• Dobson R, Hellwig K. Use of disease-modifying drugs during pregnancy and breastfeeding. Curr Opin Neurol. 2021;34:303–311.
   PubMed Web of Science ®Google Scholar
• Ferraro D, Simone AM, Adani G, et al. Definitive childlessness in women with multiple sclerosis: a multicenter study. Neurol Sci. 2017;38:1453–1459.
   PubMed Web of Science ®Google Scholar
• Cil AP, Leventoğlu A, Sönmezer M, et al. Assessment of ovarian reserve and Doppler characteristics in patients with multiple sclerosis using immunomodulating drugs. J Turk Ger Gynecol Assoc. 2009;10:213–219.
   PubMedGoogle Scholar
• Sepúlveda M, Ros C, Martínez-Lapiscina EH, et al. Pituitary-ovary axis and ovarian reserve in fertile women with multiple sclerosis: a pilot study. Mult Scler. 2016;22:564–568.
   PubMed Web of Science ®Google Scholar
• Cocco E, Sardu C, Gallo P, et al. Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the femims study. Mult Scler. 2008;14:1225–1233.
   PubMed Web of Science ®Google Scholar
• Cavalla P, Rovei V, Masera S, et al. Fertility in patients with multiple sclerosis: current knowledge and future perspectives. Neurol Sci. 2006;27:231–239.
   PubMed Web of Science ®Google Scholar
• Thone J, Kollar S, Nousome D, et al. serum anti-mullerian hormone levels in reproductive-age women with relapsing remitting multiple sclerosis. Mult Scler J. 2014;21:41–47.
   PubMedGoogle Scholar
• Marrie RA, Reider N, Cohen J, et al. A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. Mult Scler. 2015;21:282–293.
   PubMed Web of Science ®Google Scholar
• Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in multiple sclerosis. pregnancy in multiple sclerosis group. N. Engl. J. Med. 1998;339:285–291.
   PubMed Web of Science ®Google Scholar
• Las Heras V D, De Andres C, Tellez N, et al. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler. 2007;13:981–984.
   PubMed Web of Science ®Google Scholar
• Fernandez Liguori N, Klajn D, Acion L, et al. Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (ememar study). Mult Scler. 2009;15:555–562.
   PubMed Web of Science ®Google Scholar
• Anderson A, Krysko KM, Rutatangwa A, et al. Clinical and radiologic disease activity in pregnancy and postpartum in ms. Neurol Neuroimmunol Neuroinflamm. 2021;8(2): e959.
   PubMed Web of Science ®Google Scholar
• Hughes SE, Spelman T, Gray OM, et al. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler. 2014;20:739–746.
   PubMed Web of Science ®Google Scholar
• Villaverde-González R, Candeliere-Merlicco A, Alonso-Frías MA, et al. Discontinuation of disease-modifying treatments in multiple sclerosis to plan a pregnancy: a retrospective registry study. Mult Scler Relat Disord. 2020;46:102518.
   PubMed Web of Science ®Google Scholar
• Sepúlveda M, Montejo C, Llufriu S, et al. Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors. Mult Scler Relat Disord. 2020;38:101483.
   PubMed Web of Science ®Google Scholar
• Portaccio E, Tudisco L, Pastò L, et al. Pregnancy in multiple sclerosis women with relapses in the year before conception increases the risk of long-term disability worsening. Mult Scler. 2022;28:472–479.
   PubMed Web of Science ®Google Scholar
• Krysko KM, Rutatangwa A, Graves J, et al. Association between breastfeeding and postpartum multiple sclerosis relapses: a systematic review and meta-analysis. JAMA Neurol. 2020;77:327–338.
   PubMed Web of Science ®Google Scholar
• Laplaud DA, Leray E, Barriere P, et al. Increase in multiple sclerosis relapse rate following in vitro fertilization. Neurology. 2006;66:1280–1281.
   PubMed Web of Science ®Google Scholar
• Correale J, Farez MF, Ysrraelit MC. Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol. 2012;72:682–694.
   PubMed Web of Science ®Google Scholar
• Hellwig K, Beste C, Brune N, et al. Increased ms relapse rate during assisted reproduction technique. J Neurol. 2008;255:592–593.
   PubMed Web of Science ®Google Scholar
• Chen A, Ganor Y, Rahimipour S, et al. The neuropeptides GnRH-ii and GnRH-i are produced by human t cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs. Nat Med. 2002;8:1421–1426.
   PubMed Web of Science ®Google Scholar
• Jalkanen A, Alanen A, Airas L. Pregnancy outcome in women with multiple sclerosis: results from a prospective nationwide study in Finland. Multiple Sclerosis Journal. 2010;16(8):950–955.
   PubMed Web of Science ®Google Scholar
• MacDonald SC, McElrath TF, Hernández-Díaz S. Pregnancy outcomes in women with multiple sclerosis. Am J Epidemiol. 2019;188:57–66.
   PubMed Web of Science ®Google Scholar
• Verdru P, Theys P, D’Hooghe MB, et al. Pregnancy and multiple sclerosis: the influence on long term disability. Clin Neurol Neurosurg. 1994;96:38–41.
   PubMed Web of Science ®Google Scholar
• D’Hooghe MB, Nagels G, Uitdehaag BM. Long-term effects of childbirth in ms. J Neurol Neurosurg Psychiatry. 2010;81:38–41.
   PubMed Web of Science ®Google Scholar
• Masera S, Cavalla P, Prosperini L, et al. Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis. Mult Scler. 2015;21:1291–1297.
   PubMed Web of Science ®Google Scholar
• Jokubaitis VG, Spelman T, Kalincik T, et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol. 2016;80:89–100.
   PubMed Web of Science ®Google Scholar
• Achiron A, Ben-David A, Gurevich M, et al. Parity and disability progression in relapsing-remitting multiple sclerosis. J Neurol. 2020;267:3753–3762.
   PubMed Web of Science ®Google Scholar
• Zuluaga MI, Otero-Romero S, Rovira A, et al. Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis. Neurology. 2019;92:e1507–e16.
   PubMed Web of Science ®Google Scholar
• Stenager E, Stenager EN, Jensen K. Effect of pregnancy on the prognosis for multiple sclerosis. a 5-year follow up investigation. Acta Neurol Scand. 1994;90:305–308.
   PubMed Web of Science ®Google Scholar
• D’Amico E, Leone C, Patti F. Offspring number does not influence reaching the disability’s milestones in multiple sclerosis: a seven-year follow-up study. Int J Mol Sci. 2016;17:234.
   PubMed Web of Science ®Google Scholar
• Law PP, Holland ML, Blewitt M. DNA methylation at the crossroads of gene and environment interactions. Essays Biochem. 2019;63:717–726.
   PubMed Web of Science ®Google Scholar
• Greer JM, McCombe PA. Epigenetic mechanisms and processes- role in autoimmune disorders. Biol targ ther. 2012;6:307–327.
   Google Scholar
• Mehta D, Wani S, Wallace L, et al. Cumulative influence of parity-related genomic changes in multiple sclerosis. J Neuroimmunol. 2018;328:38–49.
   PubMed Web of Science ®Google Scholar
• McCombe PA, Greer JM, Mackay IR. Sexual dimorphism in autoimmune disease. Curr Mol Med. 2009;9:1058–1079.
   PubMed Web of Science ®Google Scholar
• Georgiev D, Hamberg K, Hariz M, et al. gender differences in parkinson’s disease: a clinical perspective. Acta Neurol Scand. 2017;136:570–584.
   PubMed Web of Science ®Google Scholar
• Podcasy JL, Epperson CN. Considering sex and gender in Alzheimer's disease and other dementias. Dialogues Clin Neurosci. 2016;18:437–446.
   PubMed Web of Science ®Google Scholar
• Haaxma CA, Bloem BR, Borm GF, et al. gender differences in parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78:819–824.
   PubMed Web of Science ®Google Scholar
• Rosenkrantz TS, Hussain Z, Fitch RH. Sex differences in brain injury and repair in newborn infants: clinical evidence and biological mechanisms. Front Pediatr. 2019;7:211.
   PubMed Web of Science ®Google Scholar
• Guillemin F, Baumann C, Epstein J, et al. Older age at multiple sclerosis onset is an independent factor of poor prognosis: a population-based cohort study. Neuroepidemiology. 2017;48:179–187.
   PubMed Web of Science ®Google Scholar
• Ivaniuk A, Solodovnikova Y, Marusich T, et al. The impairment of the functional system and fatigue at the onset of the disease predict reaching disability milestones in relapsing-remitting multiple sclerosis differently in female and male patients. Acta Neurol Belg. 2020;121:1699–1706.
   PubMed Web of Science ®Google Scholar
• Mank JE. Sex chromosomes and the evolution of sexual dimorphism: lessons from the genome. Am Nat. 2009;173:141–150.
   PubMed Web of Science ®Google Scholar
• Torgrimson BN, Minson CT. Sex and gender: what is the difference? J Appl Physiol. 2005;99:785–787.
   PubMed Web of Science ®Google Scholar
• Fairbairn DJ. Sexual Dimorphism. In: Kliman R, editor. The encyclopedia of evolutionary biology. San Diego: Elsevier Science and Technology; 2016. p. 105–113.
   Google Scholar
• Verbrugge LM, Wingard DL. Sex differentials in health and mortality. Women Health. 1987;12:103–145.
   PubMed Web of Science ®Google Scholar
• Eskes T, Haanen C. Why do women live longer than men? Eur J Obstet Gynecol Reprod Biol. 2007;133:126–133.
   PubMed Web of Science ®Google Scholar
• Gal-Oz ST, Maier B, Yoshida H, et al. Immgen report: sexual dimorphism in the immune system transcriptome. Nat Commun. 2019;10:4295.
   PubMed Web of Science ®Google Scholar
• Kelly CD, Stoehr AM, Nunn C, et al. Sexual dimorphism in immunity across animals: a meta-analysis. Ecol Lett. 2018;21:1885–1894.
   PubMed Web of Science ®Google Scholar
• Nunn CL, Lindenfors P, Pursall ER, et al. On sexual dimorphism in immune function. Philos Trans R Soc Lond B Biol Sci. 2009;364:61–69.
   PubMed Web of Science ®Google Scholar
• Yan J, Greer JM, Hull R, et al. The effect of ageing on human lymphocyte subsets: comparison of males and females. Immun Ageing. 2010;7(4): DOI:https://doi.org/10.1186/1742-4933-7-4.
   Google Scholar
• McCombe PA, Greer JM. Sexual dimorphism in the immune system. In: Rose NRM,IR, editor. The autoimmune diseases. London: Academic Press; 2020. p. 419–428.
   Google Scholar
• Gupte R, Brooks W, Vukas R, et al. Sex differences in traumatic brain injury: what we know and what we should know. J Neurotrauma. 2019;36:3063–3091.
   PubMed Web of Science ®Google Scholar
• Olivan S, Calvo AC, Manzano R, et al. Sex differences in constitutive autophagy. Biomed Res Int. 2014;2014:652817.
   PubMed Web of Science ®Google Scholar
• Demarest TG, McCarthy MM. Sex differences in mitochondrial (Dys)function: implications for neuroprotection. J Bioenerg Biomembr. 2015;47:173–188.
   PubMed Web of Science ®Google Scholar
• Kalimon OJ, Sullivan PG. Sex differences in mitochondrial function following a controlled cortical impact traumatic brain injury in rodents. Front Mol Neurosci. 2021;14:753946.
   PubMed Web of Science ®Google Scholar
• Cerghet M, Skoff RP, Bessert D, et al. Proliferation and death of oligodendrocytes and myelin proteins are differentially regulated in male and female rodents. J Neurosci. 2006;26:1439–1447.
   PubMed Web of Science ®Google Scholar
• Avila M, Bansal A, Culberson J, et al. the role of sex hormones in multiple sclerosis. Eur Neurol. 2018;80:93–99.
   PubMed Web of Science ®Google Scholar
• Ysrraelit MC, Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology. 2019;156:9–22.
   PubMed Web of Science ®Google Scholar
• Collongues N, Patte-Mensah C, De Seze J, et al. Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics. Expert Rev Neurother. 2018;18:515–522.
   PubMed Web of Science ®Google Scholar
• Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17:367–388.
   PubMed Web of Science ®Google Scholar
• Tait AS, Butts CL, Sternberg EM. The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease. J Leukoc Biol. 2008;84:924–931.
   PubMed Web of Science ®Google Scholar
• Chitnis T. The role of testosterone in Ms risk and course. Mult Scler. 2018;24:36–41.
   PubMed Web of Science ®Google Scholar
• Bove R, Musallam A, Healy BC, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler. 2014;20:1584–1592.
   PubMed Web of Science ®Google Scholar
• Sicotte NL, Giesser BS, Tandon V, et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol. 2007;64:683–688.
   PubMed Web of Science ®Google Scholar
• Kurth F, Luders E, Sicotte NL, et al. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin. 2014;4:454–460.
   PubMed Web of Science ®Google Scholar
• Sicotte NL, Liva SM, Klutch R, et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 2002;52:421–428.
   PubMed Web of Science ®Google Scholar
• Midaglia L, Otero S, Baró F, et al. Menopause and multiple sclerosis: influence on prognosis and role of disease-modifying drugs and hormonal replacement therapy. Mult Scler. 2022;28(2):173–82.
   Web of Science ®Google Scholar
• Balaton BP, Dixon-mcdougall T, Peeters SB, et al. The exceptional nature of the X chromosome. Hum Mol Genet. 2018;27:R242–r9.
   PubMed Web of Science ®Google Scholar
• Maan AA, Eales J, Akbarov A, et al. The Y chromosome: a blueprint for men’s health? Eur J Human Genet. 2017;25:1181–1188.
   PubMed Web of Science ®Google Scholar
• Case LK, Wall EH, Dragon JA, et al. The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Res. 2013;23:1474–1485.
   PubMed Web of Science ®Google Scholar
• Alves NL, Arosa FA, van Lier RA. Common gamma chain cytokines: dissidence in the details. Immunol Lett. 2007;108:113–120.
   PubMed Web of Science ®Google Scholar
• Costantino CM, Baecher-Allan C, Hafler DA. multiple sclerosis and regulatory T cells. J Clin Immunol. 2008;28:697–706.
   PubMed Web of Science ®Google Scholar
• Piatek P, Namiecinska M, Domowicz M, et al. Multiple sclerosis CD49d(+)CD154(+) as myelin-specific lymphocytes induced during remyelination. Cells. 2019;9:15.
   Web of Science ®Google Scholar
• Boziki M, Grigoriadis N. An update on the role of matrix metalloproteinases in the pathogenesis of multiple sclerosis. Med Chem. 2018;14:155–169.
   PubMed Web of Science ®Google Scholar
• Consortium IMSG. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365:(6460): eaav7188.
   PubMed Web of Science ®Google Scholar
• Seminog OO, Seminog AB, Yeates D, et al. Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity. 2015;48:125–128.
   PubMed Web of Science ®Google Scholar
• Youness A, Miquel CH, Guéry JC. Escape from X chromosome inactivation and the female predominance in autoimmune diseases. Int J Mol Sci. 2021;22:1114.
   PubMed Web of Science ®Google Scholar
• Smith-Bouvier DL, Divekar AA, Sasidhar M, et al. A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med. 2008;205:1099–1108.
   PubMed Web of Science ®Google Scholar
• Ebers GC, Kukay K, Bulman DE, et al. A full genome search in multiple sclerosis. Nat Genet. 1996;13:472–476.
   PubMed Web of Science ®Google Scholar
• Duquette P, Pleines J, Girard M, et al. The increased susceptibility of women to multiple sclerosis. Can J Neurol Sci. 1992;19:466–471.
   PubMed Web of Science ®Google Scholar
• Ramagopalan SV, Byrnes JK, Dyment DA, et al. Parent-of-origin ofHLA-DRB1*1501 and age of onset of multiple sclerosis. J Hum Genet. 2009;54:547–549.
   PubMed Web of Science ®Google Scholar
• Hall HI, May DS, Lew RA, et al. Sun protection behaviors of the U.S. white population. Prev Med. 1997;26:401–407.
   PubMed Web of Science ®Google Scholar
• Song Y, Fleet JC. 1,25 dihydroxycholecalciferol-mediated calcium absorption and gene expression are higher in female than in male mice. J Nutr. 2004;134:1857–1861.
   PubMed Web of Science ®Google Scholar
• Thomas-Ahner JM, Wulff BC, Tober KL, et al. Gender differences in Uvb-Induced skin carcinogenesis, inflammation, and DNA damage. Cancer Res. 2007;67:3468–3474.
   PubMed Web of Science ®Google Scholar
• Brown JWL, Coles A, Horakova D, et al. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. Jama. 2019;321:175–187.
   PubMed Web of Science ®Google Scholar
• Nishanth K, Tariq E, Nzvere FP, et al. Role of smoking in the pathogenesis of multiple sclerosis: a review article. Cureus. 2020;12:e9564.
   PubMed Web of Science ®Google Scholar
• Marck CH, Das Nair R, Grech LB, et al. Modifiable risk factors for poor health outcomes in multiple sclerosis: the urgent need for research to maximise smoking cessation success. Mult Scler. 2020;26:266–271.
   PubMed Web of Science ®Google Scholar
• Larsson SC, Burgess S. Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies. BMC Med. 2021;19:320.
   PubMed Web of Science ®Google Scholar
• Marrodan M, Farez MF, Balbuena Aguirre ME, et al. Obesity and the risk of multiple sclerosis. The role of leptin. Ann Clin Transl Neurol. 2021;8:406–424.
   PubMed Web of Science ®Google Scholar
• Mannino A, Lithander FE, Dunlop E, et al. A proinflammatory diet is associated with an increased likelihood of first clinical diagnosis of central nervous system demyelination in women. Mult Scler Relat Disord. 2021;57:103428.
   PubMed Web of Science ®Google Scholar
• Lassmann H, van Horssen J. The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett. 2011;585:3715–3723.
   PubMed Web of Science ®Google Scholar
• Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8:647–656.
   PubMed Web of Science ®Google Scholar
• Witte ME, Mahad DJ, Lassmann H, et al. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med. 2014;20:179–187.
   PubMed Web of Science ®Google Scholar
• Immonen E, Hamalainen A, Schuett W, et al. Evolution of sex-specific pace-of-life syndromes: genetic architecture and physiological mechanisms. Behav Ecology Sociobiol. 2018;72:60.
   PubMed Web of Science ®Google Scholar
• Greer JM, McCombe PA. Role of gender in multiple sclerosis: clinical effects and potential molecular mechanisms. J Neuroimmunol. 2011;234:7–18.
   PubMed Web of Science ®Google Scholar
• Vegeto E, Villa A, Della Torre S, et al. The role of sex and sex hormones in neurodegenerative diseases. Endocr Rev. 2020;41:273–319.
   PubMed Web of Science ®Google Scholar
• Pearse RV 2nd, Young-Pearse TL. Lost in translational biology: understanding sex differences to inform studies of diseases of the nervous system. Brain Res. 2019;1722:146352.
   PubMed Web of Science ®Google Scholar