Multiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS.

Keywords:
Multiple sclerosis, Female gender, Pregnancy, Menarche, Oral contraceptives
1.
Greer JM, McCombe PA: Role of gender in multiple sclerosis: clinical effects and potential molecular mechanisms. J Neuroimmunol 2011;234:7-18.
2.
Taylor BV: The major cause of multiple sclerosis is environmental: genetics has a minor role - yes. Mult Scler 2011;17:1171-1173.
3.
Hutchinson M: Truly benign multiple sclerosis is rare: let's stop fooling ourselves - commentary. Mult Scler 2012;18:15.
4.
Sawcer S: The major cause of multiple sclerosis is environmental: genetics has a minor role - no. Mult Scler 2011;17:1174-1175.
5.
Sawcer S, Hellenthal G, Pirinen M, et al: Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:214-219.
6.
Chao MJ, Herrera BM, Ramagopalan SV, et al: Parent-of-origin effects at the major histocompatibility complex in multiple sclerosis. Hum Mol Genet 2010;19:3679-3689.
7.
Handel AE, Giovannoni G, Ebers GC, Ramagopalan SV: Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol 2010;6:156-166.
8.
Levin LI, Munger KL, O'Reilly EJ, Falk KI, Ascherio A: Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol 2010;67:824-830.
9.
Bentzen J, Flachs EM, Stenager E, Bronnum-Hansen H, Koch-Henriksen N: Prevalence of multiple sclerosis in Denmark 1950-2005. Mult Scler 2010;16:520-525.
10.
Koch-Henriksen N, Sorensen PS: The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010;9:520-532.
11.
Vollmer T: The natural history of relapses in multiple sclerosis. J Neurol Sci 2007;256(suppl 1):S5-S13.
12.
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707-717.
13.
Patrikios P, Stadelmann C, Kutzelnigg A, et al: Remyelination is extensive in a subset of multiple sclerosis patients. Brain 2006;129:3165-3172.
14.
Trapp BD, Nave KA: Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008;31:247-269.
15.
D'Hooghe M B, Nagels G, Bissay V, De Keyser J: Modifiable factors influencing relapses and disability in multiple sclerosis. Mult Scler 2010;16:773-785.
16.
Miller DH, Leary SM: Primary-progressive multiple sclerosis. Lancet Neurol 2007;6:903-912.
17.
Confavreux C, Vukusic S, Moreau T, Adeleine P: Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.
18.
Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y: Impact of multiple sclerosis relapses on progression diminishes with time. Neurology 2009;73:1616-1623.
19.
Scalfari A, Neuhaus A, Daumer M, Ebers GC, Muraro PA: Age and disability accumulation in multiple sclerosis. Neurology 2011;77:1246-1252.
20.
Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444-1452.
21.
Confavreux C, Vukusic S, Adeleine P: Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003;126:770-782.
22.
Leray E, Yaouanq J, Le Page E, et al: Evidence for a two-stage disability progression in multiple sclerosis. Brain 2010;133:1900-1913.
23.
Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers GC: 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.
24.
Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O: The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol 2011;122:155-170.
25.
Filippi M, Rocca MA: MR imaging of multiple sclerosis. Radiology 2011;259:659-681.
26.
Vigeveno RM, Wiebenga OT, Wattjes MP, Geurts JJ, Barkhof F: Shifting imaging targets in multiple sclerosis: from inflammation to neurodegeneration. J Magn Reson Imaging 2012;36:1-19.
27.
Li DK, Held U, Petkau J, et al: MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology 2006;66:1384-1389.
28.
Myhr KM, Mellgren SI: Corticosteroids in the treatment of multiple sclerosis. Acta Neurol Scand Suppl 2009;73-80.
29.
Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R: Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol 2008;255:1449-1463.
30.
Cohen JA, Barkhof F, Comi G, et al: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-415.
31.
Polman CH, O'Connor PW, Havrdova E, et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910.
32.
Inglese M, Benedetti B, Filippi M: The relation between MRI measures of inflammation and neurodegeneration in multiple sclerosis. J Neurol Sci 2005;233:15-19.
33.
Orton SM, Herrera BM, Yee IM, et al: Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006;5:932-936.
34.
Chitnis T, Glanz B, Jaffin S, Healy B: Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler 2009;15:627-631.
35.
Duquette P, Murray TJ, Pleines J, et al: Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr 1987;111:359-363.
36.
Ghezzi A, Deplano V, Faroni J, et al: Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 1997;3:43-46.
37.
Cossburn M, Ingram G, Hirst C, Ben-Shlomo Y, Pickersgill TP, Robertson NP: Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis. Mult Scler 2012;18:45-54.
38.
Bove RM, Healy B, Augustine A, Musallam A, Gholipour T, Chitnis T: Effect of gender on late-onset multiple sclerosis. Mult Scler 2012;18:1472-1479.
39.
Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 1989;112:1419-1428.
40.
Fazekas F, Enzinger C, Wallner-Blazek M, Ropele S, Pluta-Fuerst A, Fuchs S: Gender differences in MRI studies on multiple sclerosis. J Neurol Sci 2009;286:28-30.
41.
Schoonheim MM, Hulst HE, Landi D, et al: Gender-related differences in functional connectivity in multiple sclerosis. Mult Scler 2012;18:164-173.
42.
Schoonheim MM, Popescu V, Rueda Lopes FC, et al: Subcortical atrophy and cognition: sex effects in multiple sclerosis. Neurology 2012;79:1754-1761.
43.
Li DK, Zhao GJ, Paty DW: Randomized controlled trial of interferon-β1a in secondary progressive MS: MRI results. Neurology 2001;56:1505-1513.
44.
French J, Gronseth G: Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634-1638.
45.
Scholten-Peeters GG, Verhagen AP, Bekkering GE, et al: Prognostic factors of whiplash-associated disorders: a systematic review of prospective cohort studies. Pain 2003;104:303-322.
46.
Ramagopalan SV, Valdar W, Criscuoli M, et al: Age of puberty and the risk of multiple sclerosis: a population-based study. Eur J Neurol 2009;16:342-347.
47.
D'Hooghe MB, Haentjens P, Nagels G, D'Hooghe T, De Keyser J: Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis. J Neurol 2012;259:855-861.
48.
Zorgdrager A, De Keyser J: The premenstrual period and exacerbations in multiple sclerosis. Eur Neurol 2002;48:204-206.
49.
Thorogood M, Hannaford PC: The influence of oral contraceptives on the risk of multiple sclerosis. Br J Obstet Gynaecol 1998;105:1296-1299.
50.
Hernan MA, Hohol MJ, Olek MJ, Spiegelman D, Ascherio A: Oral contraceptives and the incidence of multiple sclerosis. Neurology 2000;55:848-854.
51.
Alonso A, Jick SS, Olek MJ, Ascherio A, Jick H, Hernan MA: Recent use of oral contraceptives and the risk of multiple sclerosis. Arch Neurol 2005;62:1362-1365.
52.
Poser S, Raun NE, Wikstrom J, Poser W: Pregnancy, oral contraceptives and multiple sclerosis. Acta Neurol Scand 1979;59:108-118.
53.
Sena A, Couderc R, Vasconcelos JC, Ferret-Sena V, Pedrosa R: Oral contraceptive use and clinical outcomes in patients with multiple sclerosis. J Neurol Sci 2012;317:47-51.
54.
Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T: Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 1998;339:285-291.
55.
Hutchinson M: Pregnancy in multiple sclerosis. J Neurol Neurosurg Psychiatry 1993;56:1043-1045.
56.
Roullet E, Verdier-Taillefer MH, Amarenco P, Gharbi G, Alperovitch A, Marteau R: Pregnancy and multiple sclerosis: a longitudinal study of 125 remittent patients. J Neurol Neurosurg Psychiatry 1993;56:1062-1065.
57.
Paavilainen T, Kurki T, Parkkola R, et al: Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis. Eur J Neurol 2007;14:1216-1221.
58.
Lebrun C, Le Page E, Kantarci O, Siva A, Pelletier D, Okuda D: Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler 2012;18:1297-1302.
59.
Portaccio E, Ghezzi A, Hakiki B, et al: Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 2011;77:145-150.
60.
Nelson LM, Franklin GM, Jones MC: Risk of multiple sclerosis exacerbation during pregnancy and breast-feeding. JAMA 1988;259:3441-3443.
61.
Achiron A, Kishner I, Dolev M, et al: Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J Neurol 2004;251:1133-1137.
62.
Langer-Gould A, Huang SM, Gupta R, et al: Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol 2009;66:958-963.
63.
Hellwig K, Haghikia A, Rockhoff M, Gold R: Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord 2012;5:247-253.
64.
Ramagopalan S, Yee I, Byrnes J, Guimond C, Ebers G, Sadovnick D: Term pregnancies and the clinical characteristics of multiple sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 2012;83:793-795.
65.
Koch M, Uyttenboogaart M, Heersema D, Steen C, De Keyser J: Parity and secondary progression in multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:676-678.
66.
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.
67.
Verdru P, Theys P, D'Hooghe MB, Carton H: Pregnancy and multiple sclerosis: the influence on long-term disability. Clin Neurol Neurosurg 1994;96:38-41.
68.
D'Hooghe M B, Nagels G, Uitdehaag BM: Long-term effects of childbirth in MS. J Neurol Neurosurg Psychiatry 2010;81:38-41.
69.
Keyhanian K, Davoudi V, Etemadifar M, Amin M: Better prognosis of multiple sclerosis in patients who experienced a full-term pregnancy. Eur Neurol 2012;68:150-155.
70.
Ponsonby AL, Lucas RM, van der Mei IA, et al: Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology 2012;78:867-874.
71.
Correale J, Farez MF, Ysrraelit MC: Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol 2012 (E-pub ahead of print).
72.
Michel L, Foucher Y, Vukusic S, et al: Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry 2012;83:796-802.
73.
Laplaud DA, Leray E, Barriere P, Wiertlew-ski S, Moreau T: Increase in multiple sclerosis relapse rate following in vitro fertilization. Neurology 2006;66:1280-1281.
74.
Hellwig K, Beste C, Brune N, et al: Increased MS relapse rate during assisted reproduction technique. J Neurol 2008;255:592-593.
75.
Hellwig K, Schimrigk S, Beste C, Muller T, Gold R: Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis. Eur Neurol 2009;61:65-68.
76.
Sloka JS, Pryse-Phillips WE, Stefanelli M: The relation between menarche and the age of first symptoms in a multiple sclerosis cohort. Mult Scler 2006;12:333-339.
77.
Romeo RD: Pubertal maturation and programming of hypothalamic-pituitary-adrenal reactivity. Front Neuroendocrinol 2010;31:232-240.
78.
Gold SM, Raji A, Huitinga I, Wiedemann K, Schulz KH, Heesen C: Hypothalamo-pituitary-adrenal axis activity predicts disease progression in multiple sclerosis. J Neuroimmunol 2005;165:186-191.
79.
Zorgdrager A, De Keyser J: Menstrually related worsening of symptoms in multiple sclerosis. J Neurol Sci 1997;149:95-97.
80.
Holmqvist P, Hammar M, Landtblom AM, Brynhildsen J: Symptoms of multiple sclerosis in women in relation to cyclical hormone changes. Eur J Contracept Reprod Health Care 2009;14:365-370.
81.
Pozzilli C, Falaschi P, Mainero C, et al: MRI in multiple sclerosis during the menstrual cycle: relationship with sex hormone patterns. Neurology 1999;53:622-624.
82.
Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD: Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis. Acta Neurol Scand 1999;99:91-94.
83.
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.
84.
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.
85.
Grinsted L, Heltberg A, Hagen C, Djursing H: Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis. J Intern Med 1989;226:241-244.
86.
Falaschi P, Martocchia A, Proietti A, D'Urso R, Antonini G: High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis. Neuroendocrinol Lett 2001;22:248-250.
87.
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.
88.
Holmqvist P, Hammar M, Landtblom AM, Brynhildsen J: Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis. Fertil Steril 2010;94:2835-2837.
89.
Baroncini M, Jissendi P, Catteau-Jonard S, et al: Sex steroid hormones-related structural plasticity in the human hypothalamus. Neuroimage 2010;50:428-433.
90.
El-Etr M, Ghoumari A, Sitruk-Ware R, Schumacher M: Hormonal influences in multiple sclerosis: new therapeutic benefits for steroids. Maturitas 2011;68:47-51.
91.
Heesen C, Gold SM, Huitinga I, Reul JM: Stress and hypothalamic-pituitary-adrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis - a review. Psychoneuroendocrinology 2007;32:604-618.
92.
Poser S, Poser W: Multiple sclerosis and gestation. Neurology 1983;33:1422-1427.
93.
Neuteboom RF, Janssens AC, Siepman TA, et al: Pregnancy in multiple sclerosis: clinical and self-report scales. J Neurol 2012;259:311-317.
94.
Vukusic S, Hutchinson M, Hours M, et al: Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain 2004;127:1353-1360.
95.
Gilli F, Lindberg RL, Valentino P, et al: Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS One 2010;5:e8962.
96.
Gilli F, Navone ND, Perga S, et al: Loss of braking signals during inflammation: a factor affecting the development and disease course of multiple sclerosis. Arch Neurol 2011;68:879-888.
97.
Weinshenker BG, Hader W, Carriere W, Baskerville J, Ebers GC: The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middlesex County, Ontario. Neurology 1989;39:1438-1440.
98.
Thompson DS, Nelson LM, Burns A, Burks JS, Franklin GM: The effects of pregnancy in multiple sclerosis: a retrospective study. Neurology 1986;36:1097-1099.
99.
Dahl J, Myhr KM, Daltveit AK, Hoff JM, Gilhus NE: Pregnancy, delivery, and birth outcome in women with multiple sclerosis. Neurology 2005;65:1961-1963.
100.
Dahl J, Myhr KM, Daltveit AK, Gilhus NE: Pregnancy, delivery and birth outcome in different stages of maternal multiple sclerosis. J Neurol 2008;255:623-627.
101.
Van der Kop ML, Pearce MS, Dahlgren L, et al: Neonatal and delivery outcomes in women with multiple sclerosis. Ann Neurol 2011;70:41-50.
102.
Dorotta IR, Schubert A: Multiple sclerosis and anesthetic implications. Curr Opin Anaesthesiol 2002;15:365-370.
103.
Bader AM, Hunt CO, Datta S, Naulty JS, Ostheimer GW: Anesthesia for the obstetric patient with multiple sclerosis. J Clin Anesth 1988;1:21-24.
104.
Sicotte NL, Liva SM, Klutch R, et al: Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 2002;52:421-428.
105.
Vukusic S, Ionescu I, El-Etr M, et al: The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement. J Neurol Sci 2009;286:114-118.
106.
Holmqvist P, Wallberg M, Hammar M, Landtblom AM, Brynhildsen J: Symptoms of multiple sclerosis in women in relation to sex steroid exposure. Maturitas 2006;54:149-153.
107.
Smith R, Studd JW: A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J R Soc Med 1992;85:612-613.
108.
Schmidt KL, Pradhan DS, Shah AH, Charlier TD, Chin EH, Soma KK: Neurosteroids, immunosteroids, and the Balkanization of endocrinology. Gen Comp Endocrinol 2008;157:266-274.
109.
Luchetti S, Huitinga I, Swaab DF: Neuro-steroid and GABA-A receptor alterations in Alzheimer's disease, Parkinson's disease and multiple sclerosis. Neuroscience 2011;191:6-21.
110.
Leitner H: Influence of neurosteroids on the pathogenesis of multiple sclerosis. Med Hypotheses 2010;75:229-234.
111.
Noorbakhsh F, Ellestad KK, Maingat F, et al: Impaired neurosteroid synthesis in multiple sclerosis. Brain 2011;134:2703-2721.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.