Whe 10 69

Review
Gender issues in multiple sclerosis:

an update
Céline Jobin1, Catherine Larochelle1, Hélène Parpal1, Patricia K Coyle2
& Pierre Duquette†1
Although multiple sclerosis (MS) affects both women and men, women are more susceptible to
MS than men. Accumulating evidence indicates that the incidence and prevalence of MS is
increasing, more so in women than in men. Owing to pregnancy, differing hormonal states and
distinct social roles, the impact of MS differs between women and men. Since Patricia K Coyle
published a review on gender issues in MS, multiple studies have added to the body of knowledge.
This update will summarize the current thinking on gender-related issues in MS and we will address
incidence and prevalence, hormonal factors, pregnancy and breastfeeding, genetics, course and
prognosis, imaging, treatment and psychosocial aspects. Future progression within this field will
help elucidate the cause of and define the treatment of MS.
Gender issues in multiple sclerosis (MS) are at the published between 1966 and 2007) reported an
forefront of current research since Patricia K Coyle overall incidence rate of 3.6 per 100,000 per‑
authored a paper on the matter [1] . The reader is sons per year in women, versus 2.0 in men. The
advised that this paper will be an update of that incidence of the sex ratio had increased over
previous document. The most striking new data time, from 1.4 in 1955 to 2.3 in 2000 [4] . For
involves accumulating evidence for an increas‑ each 5‑year period the incidence of the sex ratio
ing incidence and prevalence of MS over the last increased by 6%. The highest incidence was
decades, particularly among women [2] . The ratio recorded in an Italian study (12.4 per 100,000
of women to men (hereafter designated as the sex person-years in women and 7.0 in men). The
ratio), during the course of the 20th century has age-adjusted rates used the world population
increased from 1:1 to 3.5:1 according to Ebers [2] . as standard [4,5] . The highest sex ratios were
Such a rapid rise cannot result from genetic muta‑ obtained in Australia, European countries
tions, which require time. It presumably reflects (Finland, Scotland, England, Italy, Spain and
changes in the environment (internal or external), Yugoslavia) and in the USA. No Canadian study
the identification of which should shed consider‑ was included in that review [4] ; however, the
able light on the cause(s) of MS. We will also situation is similar in Canada [6] . Other stud‑
review new data on the sexual dimorphism of the ies also report an increasing incidence of MS in
brain (for humans and mammals), on the genetic women, with either a lower increase [7–20] , sta‑ 1
CHUM Notre-Dame, 1560, rue
underpinning of MS, on pregnancy and breast‑ bilization [21–25] or even decreased incidence in Sherbrooke Est, Montréal H2L 4M1,
Canada
feeding, on cognition, on imaging, on treatments men [26] . Environmental factors would probably 2
Department of Neurology, HSC T-12,
and on psychosocial issues. The importance of explain this change, since no new genetic input Rm020, Stony Brook University
the cross-talk between hormonal, immune and has been observed in these populations. Medical Center, Stony Brook, NY
11794-8121, USA
nervous systems is increasingly recognized. †
Author for correspondence:
Prevalence Tel.: +1 148 908 000 ext. 26848
[email protected]
Epidemiology The overall prevalence of MS has also increased.
It is still unknown whether MS is a primary A systematic review conducted in 2001 found
immune-mediated disorder. No critical auto‑ 400 prevalence studies. The ability to compare Keywords
antigen target has ever been identified, and it prevalence studies depends on several fac‑
remains possible that MS could represent a per‑ tors, including the variability of the surveyed • disease course • gender
• genetics • hormonal factors
sistent infectious, metabolic or neurodegenera‑ populations (e.g., size, age, structure, ethnic
• incidence • multiple sclerosis
tive process [3] . Nevertheless, as is usual for most origin and composition), the thoroughness of • pregnancy • prevalence
autoimmune/immune-mediated disorders, MS is case ascertainment, and the criteria used for • psychosocial issues • treatment
more common among women than among men. diagnosis [27] . Greater survival will contribute
to increasing prevalence [28] . Even when tak‑
Incidence ing all of these factors into account, they are part of
In 2008, a systematic review on the temporal insufficient to explain the growing prevalence
trends in MS incidence (based on 38 studies of MS cases worldwide, since initial studies in
10.2217/WHE.10.69 © 2010 Future Medicine Ltd Women's Health (2010) 6(6), 797–820 ISSN 1745-5057 797
review – Jobin, Larochelle, Parpal, Coyle & Duquette
1929. This increase has been attributed in large Latitudinal gradient

part to an increased incidence/prevalence in A latitudinal gradient has been widely reported
women [28] . for MS [41–47] . Recently, however, it has been
From 1870 to 1910, opinions varied on questioned [4,22,27,32,48] . When looking at dif‑
whether men or women were more affected by ferences between sexes in this gradient, a review
MS [29] . In 1921, Wechsler analyzed 1970 patient conducted in 2008 reported that before 1980
records, and concluded that men were more fre‑ a 10° increment in latitude was associated
quently affected than women by a ratio of 3:2. with a 31% increase in MS incidence among
By 1940, almost all studies agreed that women women, and a 54% increase among men.
were more affected. A slightly higher incidence After 1980, the corresponding numbers were
in women was reported by Schumacher in 15% among women and 11% among men [4] .
1960 [29] . In a study published in 1980, women The latitudinal gradient parallels the degree
represented 60% of MS patients (n = 349) [30] . of sun exposure, and has been attributed to
Most studies from Canada [13,28] , the vitamin D deficiency.
USA [22,31–33] , Italy [9] , the UK [23] , France [24] ,
Norway [10] , Finland [12] , Denmark [25] , Basic biology
Australia [21,34] , Japan [35] and South Sex hormones
America [36,37] report an increase of MS preva‑ Mammalian sexual differentiation was assumed
lence solely, or predominantly among women, to be initiated by the presence or absence of the
resulting in a higher sex ratio. Only one small testis-determining factor SRY, encoded on the
study reported a decrease in sex ratio among MS Y chromosome. SRY induces the production
patients (F igur e 1) [9,10,12,13,21,23,33,34,37,38,39,40] . of testes, which secrete the hormones respon‑
The Canadian Collaborative Project on the sible for male secondary sexual differentiation.
Genetic Susceptibility to MS (CCPGSMS) However, female development is not only car‑
reviewed a cohort of 29,478 MS patients ried out by default, since recent studies suggest
(21,054 women and 8424 men) born between that both Y and X sex-chromosomal primary
1891 and 1993, and analyzed sex ratios by years mechanisms of sex determination are involved.
of birth. It was found that with each year the In addition, sex-chromosomal genes can influ‑
sex ratio increased by a factor of 1.014, which ence not only the development of nongonadal
corresponds to a 0.85% increase per year. The secondary sexual organs, but also of other organs
MS sex ratio changed from 1.90 to 3.21 in such as the brain.
births between 1931–1935 and 1976–1980, Sex hormones are essential for neural circuit
and is now expected to exceed 3.5. Logistic development [49] . Testosterone activates the
regression analysis showed the year of birth androgen receptor. It is converted into estro‑
to be a significant predictor for sex ratio [28] . gen in the brain via aromatase, or to dihydro
The same group compared sex ratios by year testosterone by 5a-reductase. Estradiol and
of birth among immigrants versus Canadian- dihydrotestosterone then act on estrogen and
born individuals. The approximate overall per‑ testosterone receptors respectively, to shape the
centage rate increase every 10 years was 3.13% brain. Extensive sexual dimorphism has been
for the former, and 2.82% years for the latter. demonstrated in the number and projections of
Earlier age at migration resulted in a higher sex aromatase-expressing neurons. The masculiniza‑
ratio, highlighting the impact of environmen‑ tion of these cells is independent of androgen
tal factors on MS risk [6] . Two other groups receptor, but can be induced in females by tes‑
used a similar methodology and reached con‑ tosterone or estrogen, indicating a role for aro‑
cordant results. matase in sexual differentiation of these neurons.
In summary, accumulating data documents In addition to hormones from the gonads, both
an increased incidence and prevalence of MS male and female adolescents (and adults) are
overall over the last 5 decades, especially in exposed to androgens from the adrenals, such
countries with a high prevalence. The increase as dehydroepiandrosterone. While sex hormones
seems mostly related to an increased suscepti‑ undoubtedly play an important role in the sexual
bility among women. These shifts supersede differentiation of the brain, other mechanisms
changes in diagnostic methods, access to care may be involved in this phenomenon. Indeed, the
or referral patterns, and cannot be attributed identification of genes differentially expressed in
to genetic factors. Understanding why these male and female mouse brains, even before for‑
changes occurred would shed light on the causes mation of the gonads, suggests that genetic fac‑
of MS. tors may also influence the sexual differentiation
798 www.futuremedicine.com future science group

Gender issues in multiple sclerosis – review
of the brain. One example of this is the expres‑

Phadke 1987
sion of several Y-linked genes (e.g., Usp9y) in the (Scotland, UK)
brain of male and XY female mice [50] . 4.5
Celius 2001
Gender differences in the hypothalamic– 4 (Norway)
pituitary–adrenal axis (HPA) are recognized in Simmons 2001
3.5 (Australia)
animals and humans. In response to a psycho
logical stressor, HPA responses are generally 3 Callegaro 2001
greater in males than females. The impregna‑ (Brazil)
2.5 Barnett 2003
tion of the brain by gonadal hormones dur‑
Ratio
(Australia)
ing the perinatal period helps shape the HPA 2
Sarasoja 2004
sexual dimorphism, which is maintained in 1.5 (Finland)
the adult by gonadal steroid hormone levels. Sloka 2005
It is recognized that stress and HPA, through 1 (Canada)
release of catecholamines and glucocorticoids, 0.5 Cutter 2007
affect major immune functions such as antigen (USA)
0
presentation, leukocyte proliferation and traf‑ Pugliatti 2009
ficking, secretion of cytokines and antibod‑ (Sardinia, Italy)
40
70
79
81
85
90
95
97
01
19
19
19
19
19
19
19
19
20
ies [51] . Susceptibility to autoimmune disease Hirst 2009
Year (South East Wales, UK)
may be related to an impaired responsiveness of
the HPA axis. Stressors (e.g., an infection) are Figure 1. Evolution of women:men MS ratio over time.
known to increase risk of MS relapse. Adapted from [9,10,12,13,21,23,33,34,37,39] .
The immune system is also powerfully
modulated by gender both early in develop‑ circulating concentrations of estrogen during
ment and during the perinatal period, when late pregnancy also promote prolactin secretion.
sex steroid hormones may permanently alter the As for sex steroid hormones, prolactin levels fall
developmental pattern of the T-cell repertoire after birth but are restored during breastfeed‑
in the thymus. Indeed, the immune system of ing. Breastfeeding has been shown in one study
adult males and females exhibits differences in to reduce relapse frequency, and this has been
anatomy, cytology, immunoglobulin levels and related to the duration of amenorrhea [53] . PL
responsiveness. In animal models, females have also promotes oligodendrocyte precursor prolif‑
a greater resistance to tolerance induction, as eration and stimulates myelin repair in mice [54] .
well as more pronounced tumor allograft rejec‑ PL may then act to reduce disease activity by
tion [52] . Several immune genes are believed to protecting myelin and enhancing repair [54] ,
be under the strong influence of sex hormones. presenting a potential new therapeutic avenue.
The control of regulatory T‑cell development A case has been reported in which a man with
can be considered as one of the key immune optic neuritis was found to have a PL-secreting
components of this sexual dimorphism. pituitary adenoma. Pharmacological treatment
of the adenoma resulted in a 12‑year remission.
Prolactin The ensuing clinical and MRI relapses were
Prolactin (PL) is a mammotropic neuropeptide, concomitant with a surge in the plasma levels
produced by the pituitary gland as well as of PL [55] . This case indicates that PL can have
extrapituitary tissues (e.g., the endometrium, proinflammatory effects. Other factors during
and cells of the immune system). It belongs pregnancy, in addition to estriol, exhibit anti-
to the growth and lactogenic hormone family, inflammatory properties, namely pregnancy-
which includes growth hormone and placental specific glycoproteins, a-fetoprotein, early preg‑
lactogens. Pituitary PL secretion is under hypo‑ nancy factor and relaxin (an estradiol-binding
thalamic control. The cytokines IL-1, IL-2 and protein with immunoregulatory functions).
IL-6 also stimulate PL production, while IFN-g
and endothelin-3 are inhibitory. The gene cod‑ Leptin
ing for PL is close to the MHC complex on Leptin is a pleiotropic hormone produced pri‑
the short arm of chromosome 6. PL regulates marily by adipocytes, T cells and neurons. Its
reproduction, osmoregulation, and behavior, serum levels are approximately three times higher
and has potent immunomodulatory effects. PL in females than in males. Sex steroid hormones,
increases the expression of costimulatory mol‑ testosterone in particular, are significant deter‑
ecules, as well as cytokine secretion from T, minants of the sex difference in serum leptin
B , natural killer and dendritic cells. The high levels. Leptin may contribute to experimental
future science group Women's Health (2010) 6(6) 799

allergic encephalomyelitis (EAE)/MS patho‑ electrophysiologic function in neurons, protect

genesis by acting as a proinflammatory cyto‑ oligodendrocytes from cytotoxicity, accelerate
kine promoting regulatory T cell anergy and oligodendrocyte process formation, and increase
hyporesponsiveness, leading to increased Th1 dendritic spine formation and synapses on CA1
and reduced Th2 cytokine production. In pyramidal cells of the hippocampus in rats,
relapsing-remitting multiple sclerosis (RRMS) resulting in improved memory. In vivo studies
patients (men and women analyzed together), have shown that estrogen treatment can be neu‑
circulating leptin levels are increased, and the roprotective in animal models of Parkinson’s dis‑
Treg population is decreased. Leptin plasma ease, cerebellar ataxia, late onset leukodystrophy,
concentrations are proportional to the amount stroke and spinal cord injury, often acting to
of fat tissue, so obese individuals produce higher reduce apoptosis.
levels of leptin. The increasing MS prevalence in Estrogens also exert genetic effects by regu‑
women may partially be linked to the worldwide lating gene transcription by nuclear receptors,
increasing prevalence of obesity [51] . Obesity at ERba, and ERbb, which are expressed in both
18 years of age has been reported to double the the immune system and the CNS. In addition
risk of MS [56] . to the nuclear ERs, plasma membrane-associated
ERs mediate the nongenomic signaling path‑
Protective effects way. Anti-inflammatory mechanisms of estro‑
Testosterone gens have been found to be mediated by ERa.
There is evidence for a protective effect of testos‑ Selective ERa ligand treatment also decreased
terone on the CNS (reviewed in [52]). Testosterone CNS infiltration in EAE, whereas a selective
reduces the production of inflammatory cyto‑ ERb ligand had no effect. Estriol treatment
kines such as TNF-a and IL-1b by human effects on metalloproteinase-9 bioactivity, and
macrophages. Naive T cells stimulated in vitro CNS infiltration by T cells and monocytes in
with CNS autoantigens, in the presence of testo‑ EAE were also mediated via ERa.
sterone, produce higher levels of IL-5 and IL-10,
but decreased levels of IFN-g, indicating a Th2- Treatments with sex hormones
like shift. Testosterone crosses the blood–brain It has been suggested that sex steroid supple‑
barrier, and can directly influence neural cells. mentation could be beneficial owing to their
Testosterone can protect from glutamate toxicity, immunoregulatory, anti-inf lammatory and
induce neuronal differentiation, increase neu‑ neuroprotective properties. Treatment with
rite outgrowth and protect from oxidative stress testosterone in men with MS was associated
in neuronal cell lines. Neuroprotective effects with an improvement in cognitive performance
of testosterone might be mediated through an and slowing of brain atrophy, but had no effect
increase in the expression of neurotrophic fac‑ on gadolinium-enhancing lesion numbers.
tors such as brain derived neurotrophic factor. Treatment with estriol in women with MS did
These neuroprotective effects have been reviewed have an effect on enhancing lesions [60] . Further
previously [57] . clinical trials are underway. Several new steroid
hormone analogs and synthetic selective estro‑
Estrogens gen response modulators are being developed,
Numerous reviews have described estrogen’s such as selective ERa and ERb agonists and ER
neuroprotective effects [58,59] . Protective mecha‑ modulators, lacking the undesired uterotropic
nisms of estrogen treatment (both estriol and activity. Such studies could result in the design
estradiol) in EAE depend on anti-inflamma‑ of new sex steroid-based therapeutic approaches
tory mechanisms. Estrogen treatment has been to MS.
shown to affect cytokines, chemokines, matrix
metalloproteinase-9, antigen presentation and Genetic aspects
dendritic cell function. Estrogen treatment also Epigenetics
induces Tregs in EAE. Studies using estrogen The phenotype of an individual results from
receptor (ER)-a deficient mouse strains have complex interactions between genotype and
shown that clinical protection from EAE by current, past, and ancestral environmental
estrogens depends on signaling through ERa. events (reviewed in [60]). These events result in
In vitro estrogens protect neurons in models a lifelong remodeling of our epigenomes. The
of neurodegeneration, whether induced by vast majority of common diseases (e.g., athero‑
excitotoxicity or by oxidative stress. Estrogens sclerosis, diabetes, osteoporosis, asthma, and
decrease glutamate-induced apoptosis, preserve neuropsychological and autoimmune diseases),

which are often initiated in early development, according to sex in the large cohort of the
display some degree of sex bias, which can be CCPGSMS concluded that MS is transmitted
very pronounced. This bias could be explained mostly through women [65] .
by the role of sex chromosomes, the different
regulatory pathways underlying sexual devel‑ Genetic markers
opment of most organs and the lifelong fluc‑ Several genome scans have been published in
tuating impact of sex hormones. A substantial MS cohorts. The strongest association is with
proportion of dimorphic gene expression might the following extended MHC-susceptibility
be under the control of sex-specific epigenetic haplotype: HLA-DRB5*0101-HLA-DRB*1501-
markers. Environmental factors such as social HLA-DQA1*0102-HLA-DQB1*0602. With
behavior, nutrition and chemical compounds this haplotype, the risk is increased by three for
can influence, in a gender-related manner, these heterozygotes, and by six for homozygotes. There
flexible epigenetic marks. Unfavorable program‑ is a gender imbalance: 63% of women with MS
ming could lead to various defects, along with a carry this halotype, compared with only 53% of
differing susceptibility to diseases between males men with MS [65] . This implies that genetic sus‑
and females [60] . ceptibility factors are sexually dimorphic. A study
All human tissues contain the same associated this haplotype to a more severe phe‑
25,000 genes [61] . However, only a few of these notype of MS, including: reduction in N-acetyl-
genes are expressed in a given tissue, giving aspartate within normal appearing white mat‑
rise to the phenotype. To ensure proper gene ter on MR spectroscopy (an index of neuronal
expression, the epigenetic code comprises sev‑ degeneration); increase in volume of white mat‑
eral codes: the DNA methylation code, the ter lesions; reduction in normalized brain paren‑
histone code (histone methylation, acetylation chymal volume; impairment in cognition; and a
and phosphorylation), and the coregulator code, younger age at onset [66] . The HLA-DR2DQ6
which ‘orchestrate’ the activity of the genome, haplotype has been recognized to confer suscep‑
together with RNA interference. Imprinting is tibility to MS, and is more common in women
one of the epigenetic mechanisms occurring in than in men [67] .
the gametes. In these cells the inherited imprints Two CD95 polymorphisms (which partici‑
are erased and a new one, which is maternal pate in the apoptosis process, thus regulating
or paternal specific, is established. Parental clonal expansion of T cells outside the thymus)
imprinting uses DNA methylation and histone may account for 28% of the risk among homo‑
modifications for monoallelic expression of cer‑ zygote women; by contrast, they do not increase
tain genes. The expression of these imprinted the risk of MS in men [68] .
genes is then determined according to their The SNP rs2069727, adjacent to the 3´UTR
parent of origin. Imprinting affects between 90 region of the IFN-g gene, is associated with MS
and several hundred genes. Imprinted genes are in men only; this effect is stronger in homozy‑
particularly involved in embryonic development gotes than in heterozygotes. Women with MS
and metabolism, and imprinting deregulation is have higher IFN-g expression and lower IL-5
linked to cancer, obesity, diabetes and behavioral levels in response to in vitro proteolipid protein
disorders, such as autism and bipolar disease. stimulation than men with MS or women con‑
Recent studies suggest that this epigenetic pro‑ trols. This IFN-g SNP is then associated with
gramming could sometimes be transmitted to sex bias in MS susceptibility and with expression
subsequent generations in a sex-specific manner of IFN-g in MS. Among its pleiotropic effects,
and lead to transgenerational effects. The risk IFN-g induces dendritic retraction and inhibits
of developing complex disease in offspring often synapse formation. In a variety of physiologic
depends on the sex of the affected parent. There and disease states, IFN-g levels vary by sex. A
is a clear parent-of-origin effect in MS: the risk common sex-dependent mechanism may influ‑
for maternal half-siblings is 2.35%; it is 1.31% ence a variety of disorders characterized by
for paternal half-siblings. A similar effect has chronic inflammation in which IFN-g plays a
been shown in avuncular pairs (uncles/aunts and pivotal role [69] . Despite the marked female pre‑
nephews/nieces pairs). dominance in MS, no genetic marker has yet
The Carter effect stipulates that the sex with been identified on the X chromosome [65] .
the lesser susceptibility transmits the disease The gender gap in MS may be due to the
more frequently, because of an increased genetic effects of sex hormones, genetic differences,
load. Some studies support this concept [62–64] , or a combination of the two. A nonmutu‑
however, evaluation of disease transmission ally exclusive alternative hypothesis includes

a direct genetic effect on the immune sys‑ For an individual with MS, parenthood must
tem and/or the CNS. Specific gene products, be considered thoughtfully. We advise patients
which are not induced by gonadal hormones to wait a few years after disease onset, allowing
but are expressed in a sexually dimorphic man‑ time to gauge prognosis, and to make sure that
ner, could induce gender differences in MS their marital situation is favorable. In women
pathogenesis and progression. with active disease before or during pregnancy,
it is probably advisable to start treatment right
Microchimerism after delivery. For further discussion on this
Microchimerism had been suggested as a poss aspect, the reader is referred to the ‘Impact of
ible mechanism in MS. More recent studies, pregnancy on MS’ section.
however, have not reproduced the earlier find‑
ings of an increased frequency of chimeric cells Environmental factors
in MS patients [70] . Vitamin D deficiency is endemic in cities in
northen Canada [9] . No direct evidence from
Genetic counseling affected adults implicates early-life vitamin D
Genetic counseling can now be approached in a exposure in susceptibility to MS. The increased
systematic manner. When considering pregnancy, prevalence of MS among people born in May,
MS patients and their spouse should consider might reflect maternal end-of-winter deficiencies
factors enumerated in Table 1. in vitamin D. A model integrating vitamin D
Among Caucasian populations, the rate of into genetic and environmental susceptibility
acquiring MS varies from 1–2 in 1000 people. in MS postulates that vitamin D epigenetically
A total of 20% of MS patients will have another modifies genes important in the development of
affected individual among their family mem‑ the brain, immune system, or development of
bers. MS is not transmitted in a Mendelian axonal resilience or immunological tolerance [2] .
pattern, although the risk is proportional to Vitamin D deficiency has been implicated in
the degree of gene-sharing. Children from the likelihood of developing autoimmune dis‑
families with a bilinear history of MS have the eases. Autoimmune diseases are more prevalent
maximum risk of MS. The risk then gradu‑ in women, raising the possibility that women
ally decreases in the case of the homozygotic have lower vitamin D availability, or that gen‑
twin (although the risk is higher if the twins der differences in the physiological responses to
are female), then in the case of children born to vitamin D may be present. Interestingly, gender-
consanguineous parents, then the heterozygotic specific differences in vitamin D metabolism
twin, and continues to decrease in the cases of are reported. Besides its calcium homeostatic
first-, second- and third-degree relatives of the role and antineoplastic properties, vitamin D is
affected individual (see Figure 2 ) [71] . involved in the development and the maturation
It is uncommon (estimated at 20%) for MS of immunity [72] .
patients to renounce having children because Several studies have established that smoking
of the risk of disease transmission; some increases the risk of MS [73] ; in some, smoking
would rather consider adoption. Pregnancy worsens disease course. Rodriguez Regal et al.
issues are discussed later in a separate section. conducted a study on 138 MS patients and
Documentation on the possible consequences of found that smokers and ex-smokers had a 27%
MS therapies on children born to parents with increased risk of developing MS [74] . The rela‑
MS does not exist at present. A prospective MS tion was found to be significant for women but
pregnancy registry is currently in preparation. not for men.
Table 1. Considerations for parenthood in patients with multiple sclerosis.

Considerations For mothers with MS For fathers with MS
Risk of transmission to the child X X
Treatment cessation X –
Fertility X X
Pregnancy outcome X –
Loss of autonomy X X
Loss of income X X
MS: Multiple sclerosis.

Clinical presentation 35
Diagnosis delay
The mean duration between clinical onset and 30
diagnosis of MS in Canada is the same for men and
women, with a mean of 3 years in each group [28] . 25
Recurrence risk (%)

These data are based on a cohort of more than
26,000 patients (from CCPGSMS), with a mean 20
age at onset of 30 years [75] . In a group from Sicily,
15
Italy, the mean time from onset to diagnosis was
4.0 ± 4.6 years – almost the same for men and
10
women – in a population of 288 patients with a
mean age at onset of 31.4 years [19] . 5
Age at disease onset 0

Approximately 70% of patients experience MS
al
ee
s
d
in
S
in
ou
te
er
M
tw
tw
gr
op
en
ne
onset between the ages of 20 and 40 years [76] ,
ith
de
ic
ic
Ad
G
ui
ot
ot
w
t
ng
rs
yg
yg
and 90% experience onset between the ages of 15
ts
Fi
sa
iz
n
oz
re
D
on
on
and 50 years [1] . The mean age at onset is approxi‑
pa
C
th
mately 28–30 years [77] , with a mean age ear‑
Bo
lier in women than in men. In recent Canadian Sibling relation to index patient with MS
data [65] , age at onset is approximately 32 years
in women and 33.5 in men. Onset in men coin‑ Figure 2. Risk transmission.
cides with declining levels of testosterone [77,78] . MS: Multiple sclerosis.
Reproduced with permission from Can. J. Neurol. Sci. 28, S52–S55 [71] .
Onset in primary progressive multiple sclerosis
(PPMS) occurs approximately 10 years later than this course [92] . A benign course is more often
RRMS [77] , at approximately 38–41 years of age, associated with female gender [89,93–97] , although
compared with 28–30 years of age for RRMS [1] . it may not be a predictive factor [98,99] . Women
are less represented in late-onset MS [97] in which
Course of the disease the sex ratio is 1.73 :1 [100] . Perimenopausal onset
Gender influences MS course (see Coyle [1]). In of MS in women is associated with PPMS [95] .
concordant parent–child pairs with MS, male
offspring of affected fathers are more likely to Symptoms at onset & during the course
have PPMS (odds ratio [OR]: 1.92) [79] . of the disease
Two large cohort studies observed that 80–87% In PPMS there is no difference between the sexes
of MS patients have the RRMS course initially in terms of onset symptoms, except for a trend
[80–82] . RRMS is characterized by female prepon‑ for men to present more often with cerebellar or
derance with a sex ratio of 3:1 [78,83–85] . A relaps‑ brainstem symptoms [85] . In RRMS, onset symp‑
ing course is followed by secondary progression toms are more frequently sensory for women,
in some 70–80% of cases over a 2-decade period and cerebellar or brainstem for men [85] . Optic
[80,82] . The sex ratio in secondary progressive mul‑ neuritis and motor symptoms at onset have been
tiple sclerosis (SPMS) is 3.2:1 [84,86] . Time from shown to have the same frequency among men
onset to SPMS was found to be twice as long as and women [85] . In concordant parent–child pairs
previously described [87,88] . Despite this result, with MS, offspring with affected fathers tended
male gender has been associated with a greater to present more often with cerebellar and cogni‑
risk of developing SPMS [89] . Evidence differs tive symptoms in comparison with those with
on whether gender can influence the timing of affected mothers [79] .
secondary progression. Two studies found no Some studies report that pain is more commonly
influence [87,90] , while another showed that men experienced by women, or is more severe [101–103] ,
reached SPMS earlier (mean time from onset to while others found no difference [104–106] . One
SPMS was 9.6 years for men and 12.8 years for study demonstrated greater pain intensity among
women), and with a higher expanded disability women [101] . Pain types can differ between men
status scale (EDSS) score [91] . and women. Among patients reporting trigeminal
A review of nine studies assessing prognostic neuralgia and pain related to spasticity, 72 and
factors for benign MS concluded that 26.7% of 33% were women [102] . By contrast, women and
MS patients had a benign course and female sex men experience disabling fatigue with the same
gave an OR of 1.28 (95% CI: 0.94–1.73) for frequency [107–109] .

Cognitive decline is greater among men with strong inverse correlation for men, and a trend
MS [77,110,111] . The performance of men in verbal for women, between progesterone and the GM
and nonverbal delayed memory, visuospatial con‑ volume in right middle temporal pole. The cor‑
struction and executive function tests, was worse relation was not convincing between testosterone
even after adjustments were made for sex differ‑ levels and sectorial GM volumes.
ences among normal controls [110] . Among men,
risk factors for severe cognitive decline included MS
older age, longer disease duration, higher EDSS Several MRI studies demonstrate that men
score, lower education level and APO-e4 allele. with RRMS or SPMS have a significantly lower
None of these have been associated with cogni‑ number of enhancing lesions [116–118] , but have
tive impairment for women [111] . However, not all a higher number of lesions evolving into ‘black
studies have found cognitive impairment differ‑ holes’, which makes them more prone to less
ences between sexes [112,113] . Cognitive fatigue is inflammatory but more destructive lesions than
similar for both genders [114] . women [116] . Women seem to have more frequent
disruption of the blood–brain barrier, consis‑
Imaging tent with a more inflammatory profile. This
Normal brain is consistent with a hormonal influence, since
Several differences in brain morphology between high estrogen/progesterone levels in women are
women and men have been documented among associated with more gadolinium-enhancing
healthy adults [115] . The main differences are lesions [119] . However, two studies failed to show
shown in Table 2 . more enhancing lesions among women with
Witte et al. observed a positive correlation MS [120,121] . Li et al. observed a slightly greater
between 17b-estradiol and the gray matter T2 burden for men [122] . Two studies found no
(GM) volume in the left superior parietal gyrus correlation between gender and either T1 and
for both sexes [115] . They also demonstrated a T2 lesion volumes, or T1:T2 lesion ratio [121,123] .
Table 2. Gender differences in brain volumes in patients with multiple sclerosis.

Brain structure Greater volume
For women For men
Total brain X
CSF X
White matter X
Gray matter X
Broca area X
Dorsolateral prefrontal cortex X
Orbitofrontal X
Superior frontal X
Medial frontal cortex X
Anterior cingulate cortex X
Paracingulate gyrus X
Wernicke area X
Temporal association cortex X
Mesial temporal lobes X
Hippocampus X
Amygdala X
Hypothalamus X
Lingual gyri X
Parietal association cortex X
Cerebellum X
Data taken from [116].

Two studies found no influence of gender diseases were women [131] . Uveitis usually occurs
on atrophy [124,125] . A study of 763 MS patients in women aged 20–50 years old [141] and has been
showed lower normalized peripheral and total associated with MS. In a large retrospective study
GM volumes for men, and a lower normalized of patients with uveitis, 1.3% had MS, 88% of
GM volume for women. Men appeared to have which were women [142] . In another study, 83%
more cerebral atrophy [121] . The same authors of patients with uveitis and MS were women [143] .
reported that the magnetization transfer ratio
and measures of diffusivity were similar for men Sleep disorders: restless legs syndrome
and women [121] . Cortical lesions, as evaluated by Sleep disorders in MS have been reviewed pre‑
double inversion recovery, were more frequently viously [144] . Numerous studies find restless
reported in men than in women (79 and 51%, leg syndrome more frequent in MS, affecting
respectively), both in the early and in the late women more than men [144–147] . Other studies
stages of the disease [126] . The overall effect of did not observe this gender difference [148–151] .
sex hormones on MRI activity remains to be Restless legs syndrome is related to iron defi‑
established in larger studies. ciency, which is more common in women during
their reproductive years.
MRI & sex hormones in MS
Magnetic resonance imaging activity is linked Psychiatric comorbidities
to different sex hormones (testosterone, estradiol Most studies report that the risk of depres‑
and progesterone) as exemplified by variations sion is greater for women [109,152–155] with MS
throughout the menstrual cycle [127] and preg‑ (OR: 1.85; 95% CI: 1.16–2.93 for women
nancy [128] . We refer readers to the original article compared with men) [109] . However, some stud‑
from Coyle [1] for details. The overall influence is ies did not find this gender influence [156–160] .
towards greater MRI activity when estradiol lev‑ Women are more likely to use antidepressant
els are high [119,127,129] and, progesterone [119,127] drugs [161,162] . The predominance of women with
and testosterone [129] levels are low. MS suffering from depression is an important
issue, since depression is the main determinant
Comorbidities for quality-of-life (QoL) perception in MS [163] .
Autoimmune diseases There is also an association between MS
Most autoimmune diseases show women pre‑ and bipolar affective disorder, which can be
ponderance [78,130] . Co-occurrence of MS and 13-times more frequent among MS patients
other autoimmune diseases has been widely than in the general population. The sex ratio
reported [131–138] . These associations have for bipolar affective disorder within a MS cohort
recently been challenged. Ramagopalan et al. was 1.17:1 [159] .
conducted a study on 5031 MS patients, 30,259 Women with MS are at an increased risk of
first-degree relatives and 2707 spousal controls, anxiety disorders (mainly generalized anxiety
and concluded that there was only a correlation disorder, obsessive compulsive disorder and
between MS and autoimmune thyroid disease panic disorder) [164] .
and pernicious anemia (they looked at ten dif‑ The rate of suicide is reported to be increased
ferent autoimmune diseases) with no gender as much as sevenfold in MS patients [165,166] in
effect [135] . comparison to the general population, without
Only a few gender-specific considerations have gender predominance [167–171] . The risk factors
been reported between MS and other autoim‑ and characteristics of suicide in MS can differ
mune diseases, but they are not uniformly sup‑ according to gender. Men tend to commit sui‑
ported. The association of autoimmune thyroid‑ cide in the fifth decade of life, generally show
itis and MS is stronger for women [136] . This moderate disability, and have often experienced
may also apply to MS patients taking immu‑ a recent deterioration. Mental disorders and pre‑
nomodulatory drugs [139] , but some evidence vious suicidal attempts are more frequent among
against this exists [140] . Somers et al. observed men [168,172] , and they more commonly use vio‑
an inverse relation between MS and rheumatoid lent suicidal methods [172] . The characteristics of
arthritis, which is stronger for men [136] . There is women who commit suicide are less distinct [172] .
conflicting evidence on the gender predisposition More often, women with MS tend to commit
to develop MS in Type 1 diabetes. One study suicide in the first year of onset [168] . A previous
reported a greater risk for men (relative risk [RR]: study showed that MS onset before the age of
4.36) than for women (RR: 2.69) [137] ; another 30 years is associated with greater risk of suicide
observed that nearly all the patients with both for men [170] .

Cancer Childhood MS
Most studies with large numbers of patients con‑ Less than 1% of MS patients experience onset
clude that the risk of cancer is decreased in MS of symptoms prior to puberty [1,77,184] , and only
patients [173–176] . Two studies [177,178] reported an 2–5% before the age of 16 years [1,77,184–189] . Most
excess of breast cancers, which could be biased pediatric MS cohorts describe female predomi‑
in part by the low parity of women with MS. nance, with sex ratios between 1.3 and 3.0 [186] .
Nielsen et al. observed that the increase of breast This ratio is also a function of age, with girls
cancers in MS does not change according to age being proportionally more affected by MS after
at first pregnancy [173] . The risk of cancer is still puberty [185,187,190] , with a sex ratio of 1:1 before
decreased for MS patients under immunomodu‑ the age of 12, and of 2:1 thereafter [191] . Another
latory treatment, but breast cancers tended to study reported a sex ratio of 1:1 at 10 years, 2.2:1
be more frequent for glatiramer acetate users, at 15 years and 2.8:1 at 20 years [192] .
although this frequency is not significant [174,175] . Clinically isolated syndrome presenting before
Lebrun et al. observed a threefold higher risk of the age of 16 is usually a monofocal event with a
cancer for patients treated with immunosuppres‑ female predominance. Multifocal events are not
sant drugs [174] . Bahmanyar et al. observed an influenced by gender [184,191,193] . Onset symp‑
increase in the number of small intestine cancers toms vary according to gender, with more girls
among men, and of urinary organs and nonmela‑ presenting with sensory disturbances or brain‑
noma skin cancers among women with MS [176] . stem dysfunction, and more boys with motor or
One study reported a significant excess of naso‑ gait disorders [193] . The risk of developing MS
pharyngeal carcinomas and brain tumors among for children who experienced optic neuritis is not
women with MS [178] . This increased frequency different according to gender [194,195] ; neither is
of tumors could be related to the frequent MRIs the risk of a second demyelinating attack after
performed in MS patients. acute disseminated encephalomyelitis [191,196] .
In pediatric MS, most studies reveal no gender
Response to treatments influence on prognosis [186,193] . One study found
(disease modifying) that the female gender was related to a higher rate
Gender differences in the effectiveness of dis‑ of severity (68% with at least three attacks, or an
ease-modifying therapies (DMTs) in RRMS EDSS ≥4.0) [197] . Duquette et al. found somewhat
are either not observed, or not explored in better outcomes for girls than boys when MS pro‑
large trials [179] . In a postmarketing study of gression started before the age of 16 years, with a
2570 RRMS patients, men were at greater risk more complete recovery from the initial episode,
of disability progression than women at 1 year a remitting course and lower disability scores [185] .
[180] and at 7 years. Men had a lesser risk of a
second relapse [181] . Prognosis
The effectiveness of natalizumab in AFFIRM Prognosis in MS depends upon several factors
and SENTINEL trials was analyzed in prespeci‑ including gender, age, initial symptoms and
fied subgroups. The response in terms of pro‑ course, degree of recovery from the first relapse,
gressive disability was significantly favorable for time from onset to the second neurological epi‑
women, with only a favorable trend for men. The sode, number of relapses in the first 5 years of
effect on relapse rate was similar for men and the disease, and time from onset to EDSS score
women [182] . of four [80,81,89] .
One post hoc analysis of PPMS patients on glat‑ In most studies assessing the prognosis in
iramer acetate (GA) suggested that men had less MS, the progression of EDSS score is worse for
disability progression when treated, compared men than for women when including all disease
with the placebo. This effect was not observed courses [1,31,77,81,87,89,95,165,198–201] . In concordant
for women [179] . Moreover, radiological outcomes parent–child pairs with MS, the highest mean
were not dependent on gender in PPMS under EDSS score was observed in male offspring of
GA treatment, nor was the response of women affected fathers [79] . The onset of MS by cerebral
and men to GA in RRMS [179] . or urinary symptoms in women was associated
A trial of IFNb-1a in SPMS failed to demon with greater progression of disability, while onset
strate a change over disability progression, but with sensory symptoms was related to a better
the response was better in women. The relapse prognosis [202] .
rate did not depend upon gender, but the imag‑ Primary progressive multiple sclerosis car‑
ing results were slightly more favorable for ries a poorer prognosis [80,81] . Moreover, some
women [183] . studies showed that men among PPMS

patients had a worse prognosis than women Canadian study found an association between
[81,179,203] but the majority of studies found no age at onset of MS and age at menarche, with
difference [85,204–207] . age at first symptoms increasing by 1.16 years for
After optic neuritis, the risk of developing MS each year increase at menarche [229] .
after 10 years in adults is related to the MRI find‑
ings, with a 22% risk if the MRI is normal, and Menstrual cycle
a 56% risk if one or more lesions are present. In Coyle has already reviewed the influences of
the normal MRI group, male gender is associ‑ the menstrual cycle on the symptoms in MS [1] .
ated with a three-times lower risk of conversion to Relapses can be associated with the premen‑
MS (hazard ratio: 0.35; 95% CI: 0.12–0.98) [208] . strual phase of the cycle [230] . Zorgdrager and
When MRI was not taken into account, MS De Keyser reported that 42% of premenopausal
developed in 74% of women and 34% of men women had relapses in the premenstrual phase,
15 years after optic neuritis [209] . Some stud‑ and, within this group, 45% of the relapses
ies reported that women have an increased risk occurred during that phase [231] .
of developing MS [192,208,210–213] although not
always significantly [214,215] . Pregnancy
In a cohort followed for 20 years after the Impact of pregnancy on MS
initial episode, MS developed in 67 out of Pregnancy can cause exacerbation of some
107 patients (63%). MS developed in 35 out autoimmune diseases, and both autoimmune
of 54 patients (65%) who initially presented diseases and immunosuppressive drugs can
with optic neuritis, 15 out of 25 (60%) with a threaten the baby’s health [70] . Therefore, preg‑
brainstem syndrome, and 17 out of 28 (61%) nancy had historically been regarded as hazard‑
with a spinal cord syndrome [216] . Data was not ous for women with MS. This is now recognized
analyzed by gender. as incorrect. The pregnancy and multiple sclero‑
Survival is mildly decreased in MS. In some sis (PRIMS) study, and many others from differ‑
studies male gender is a risk factor for earlier ent countries, have convincingly demonstrated
death [20,217–220] while other studies show equal that MS relapses are significantly less frequent
survival for both genders [169,202,221–224] . One during pregnancy, especially during the second
study revealed higher relative mortality among and third trimesters, when compared with the
women with MS in comparison to the general prepartum relapse rate [70,232–237] .
population [225] . Temporal trends in mortality A surge of relapses paralleled by increased
support a decrease in the rates, possibly better for MRI activity is observed in the first trimester
men than for women [220] . Symptoms at onset following delivery, but the relapse rate falls back
can interact with the survival differently accord‑ to the prepartum rate by the end of the first post‑
ing to gender. One study showed that men with partum year [70,128,232–235,237–239] . Moreover,
sensory symptoms at onset had a greater survival, only 30% of patients will experience relapses
while optic neuritis onset in women showed a during the first trimester postpartum; most
tendency towards greater life expectancy [220] . relapses observed are mild and may not require
treatment [duquette P, Unpublished Data] [233,240] .
Women issues At a biological level, variable results in stud‑
Puberty/menarche ies are probably due to small study numbers and
A recent study indicates that age at puberty different methods used to measure cytokine pro‑
plays a role in the likelihood of developing MS duction and identify immune cell subsets. Some
in women but not in men [226] , but the extent studies report that pregnancy in MS is associated
to which the average age of puberty differed with lower IFN-g production by peripheral blood
between women developing MS and controls lymphocytes during pregnancy, which results
was minute (12.4 vs 12.6 years). According to in an increased Th2:Th1 ratio during preg‑
that study, the relative risk of MS decreases by nancy as compared with the postpartum period
0.9 per year with increased age at puberty. [237,241–243] . One study has reported stable levels
Previous studies reported conflicting results of IFN-g throughout pregnancy and in the post‑
when examining the influence of age at men‑ partum period in MS women showing no disease
arche on the likelihood of developing MS. One activity, and increased levels during the third tri‑
small study showed that the risk of developing mester and the postpartum period in women with
MS was not associated with menarcheal age [227] , MS experiencing disease activity clinically or on
while a second showed a lower menarcheal age MRI [238] . Another study with minimal varia‑
for MS cases than for controls [228] . A more recent tions in IFN-g levels has reported contradictory

results [244] . IL-17 production has been reported postpartum surge of relapses [252] . A beneficial
as stable [245] or decreased [246] during pregnancy effect of intravenous immunoglobulin (IVIg)
in healthy women. According to one study, IL-17 administration on postpartum relapses was
was decreased during the first and second trimes‑ observed in a nonrandomized study, especially
ters in all MS pregnancies studied, but higher when started before delivery [253] . Another study
levels were observed during the third trimester reported no significant reduction in postpartum
and the postpartum period in women experienc‑ relapses with higher versus lower IVIg doses given
ing a relapse or MRI activity [238] . An increase in after delivery, especially among breastfeeding
the Treg compartment with suppressive activity women [254] . Thus, further studies are needed,
was reported in healthy pregnancy [246,247] and in since IVIg administration comes with potential
MS pregnancy [248] . According to recent studies, side-effects and a significant socioeconomic bur‑
Treg expansion is seen only in the first and sec‑ den. The ideal timing for reinstatement of DMTs
ond trimesters of MS pregnancy compared with following pregnancy is still unknown, especially
prepregnancy levels, and no difference is observed for women wishing to breastfeed. Indeed, current
between levels in late MS pregnancy compared DMTs are not considered safe during breastfeed‑
with postpartum levels [237,238] . Pregnancy in ing, however, recent studies suggest that exclusive
MS is associated with an increased percentage of breastfeeding for at least 2 months is associated
CD56 bright regulatory natural killer cells [237] . with a significant decrease in postpartum relapses
Late pregnancy is associated with a rise in [236,255,256] , although other studies have reported
serum leptin levels in MS but not healthy preg‑ no significant effect of breastfeeding on MS
nancy, followed by a greater decrease after deliv‑ activity postpartum [233,240,257,258] .
ery in MS patients compared with healthy con‑ Since no randomized controlled trial can be
trols. The relative decrease in serum leptin levels performed regarding pregnancy, evaluation of the
after delivery could correlate with pospartum long-term effect of pregnancy on MS course is a
relapses [249] . Higher prolactin levels in preg‑ challenge. The reasons for avoiding pregnancy
nancy could be associated with an increased pro‑ can be related to disease severity for some women.
liferation of oligodendrocyte precursor cells, and However, observational studies have shown no
increased remyelination [54] . effect, or a trend toward a beneficial effect of preg‑
At a transcriptional level, gene expression for nancies on time to reach an EDSS score of 6.0
several inflammation-related transcripts has been or more, or to convert to a secondary progressive
reported to revert to healthy control levels dur‑ course [233,240,259–262] .
ing early pregnancy in MS patients, and a delay
to do so could correlate with relapses during Effect of MS on pregnancy & delivery
pregnancy [250] . Spontaneous abortion could be more frequent in
The prevention of relapses following delivery women exposed to IFN-b although the number
has been a matter of debate, since no clinical of pregnancies studied is small [263–265] . No
data can predict accurately which women are at increased risk for premature delivery was reported
an increased risk [240] . Even if PRIMS reported in a Norwegian and a US study [266,267] , although,
that higher prepregnancy attack rate, greater a Taiwanese study reported a 2.25-fold increase
disability, or relapse during pregnancy indicated in premature delivery among MS women [268] .
increased risk, these criteria would identify only Premature delivery has not been associated with
a small subset of women with a 50% relapse risk, exposure to DMTs [263–265] .
and would fail to predict 85% of all relapses Women with MS present a marginal increase
occurring during the first postpartum trimester. in the risk for prenatal hospitalization, labor
Biological markers possibly predictive of a higher induction, slow progression of labor, need of
susceptibility to postpartum relapses are under instrumental assistance at delivery and cesarean-
study; for example, the level of IL-8 during first section delivery, but are otherwise no more likely
trimester [251] , or the levels of IFN-g, IL-17, Tbet, to experience other pregnancy complications
pSTAT1, pSTAT3 [238] and serum leptin [249] such as preeclampsia, postpartum hemorrhage or
in late pregnancy and postpartum. The ongo‑ premature rupture of membranes [53,266] . There
ing Prevention of Post Partum Relapses With has been reluctance from the medical commu‑
Progestin and Estradiol in Multiple Sclerosis nity to offer epidural analgesia to women with
(POPART’MUS) trial will address the poten‑ MS at time of delivery. This attitude is not sup‑
tial of hormone therapy (high-dose progestin in ported by scientific data. Epidural analgesia is
combination with endometrial protective doses safe in MS patients and it does not induce MS
of estradiol) following delivery to prevent the relapses [dahan B, Unpublished Data] [233,240] .

Effect of MS on the baby symptoms. The incidence of MS was found to be

A slight increase in intrauterine growth restric‑ 40% lower in recent users of OCs compared with
tion and lower birth weight with normal head nonusers. Another study suggested that OC use is
circumference has been observed in children associated with a decreased severity of MS symp‑
of women with MS, probably more frequently toms. Taken together, these observations suggest
when exposed to interferon in utero [53,234,264– that OCs may be beneficial for MS patients [275] .
266,268,269] . Birth defects do not seem to be more
frequent following pregnancy in MS [233,266,267] . Psychosocial issues
Even among fetuses exposed to immunomodu‑ Social support
latory agents, no significant increase in birth In MS, as for other chronic diseases, there is an
defects is reported by most studies [232,263–265,270] , increased need for social support to overcome
although numbers are small. A retrospective the difficulties accompanying the physical and
study reported an increased malformation rate social consequences of the disease. Gender and
among newborns exposed in utero to immuno‑ marital status may influence social support.
modulatory agents [271] . Exposure to interferon Wineman et al. found that women had greater
in utero does not seem to alter early development networks than men [276] . Two studies observed
of children [269] . Ideally, immunomodulatory similar social support for both genders [277,278] .
agents should be stopped before pregnancy since Gulick et al. reported that men perceived greater
safety has not been clearly demonstrated. A non- social support, in terms of affect, affirmation
negligible proportion of pregnancies in women and aid support, than women [279] . The authors
with MS are, however, unplanned. also noticed that men without spouses (com‑
pared with those with spouses) felt a higher
Menopause loss of support. Women report more available
The risk of developing RRMS symptoms declines resources, perceived social support and perceived
with and beyond menopause [1] . PPMS often availability of friends than male caregivers [280] .
begins around menopause, and the transition Moving to a nursing home usually occurs
from RRMS to SPMS is also associated with this when social support fails to meet the needs of
period of life [1] . chronically ill patient. Buchanan et al. observed
Three studies investigated changes in MS that men in nursing homes were more likely to
symptoms in association with the meno‑ be totally dependant in activities of daily living
pause, but these reports are based on a total of and have greater motor impairment, while women
172 patients (Table 3) [272–274] . tended to have better communication skills and
cognitive performance [162] . Women more com‑
Oral contraceptives & hormone monly experienced pain and were more frequently
replacement therapies depressed or anxious than men [162] . The decreased
A large prospective study from two cohorts functional status of men in nursing homes may
in the USA, the Nurse’s Health Study (NHS; underlie their greater social support, which allows
1976–1994) and the Nurse’s Health Study II them to live in the community with a greater dis‑
(NHSII; 1989–1995) did not support a lasting ability level.
protective effect of oral contraceptives (OCs) on
MS incidence, in accordance with previous stud‑ Coping
ies issued from smaller British cohorts. A recent Patients cope differently with MS according to
case–control study performed on the large British their gender. Women tend to cope better than
General Practice Research Database, analyzed men [281] . Strategies to cope with MS are similar
MS incidence in women with at least 3 years of for both genders, but, compared with women
continuous information before the date of first men use more planning strategies, which are
Table 3. Evolution of multiple sclerosis symptoms with menopause.

Study n % worsening % stabilization % improvement Ref.
Smith and Studd 19 54 38 8 [272]
(1992)
Holmqvist et al. 72 39 56 5 [273]
(2006)
Shabas et al. 81 26 42 16 [274]
(2000)

problem-focused plans than women [282] . There suggesting that men’s well-being adjusts over time,
are gender differences in the ability to cope with a while women may be more likely to experience
parent affected by MS within families. Daughters negative cumulative effects [289] . Greater social
tend to cope better than sons, independently of support has a more positive influence on satisfac‑
the gender of the affected parent. A younger age tion with life for women than for men [289] . Patti
for daughters at MS onset is associated with bet‑ et al. found that female sex was a predictive factor
ter coping. Healthy mothers and daughters tend for poor QoL among caregivers [290] . Male and
to cope better than fathers and sons with the female caregivers have different socioeconomic
increasing disability of the father [281] . stature; since men receive a higher income than
women [289] .
Conjugal life
Literature on gender differences in conjugal Employment
life in MS is limited. There is no consensus on There is conflicting data regarding the influ‑
whether divorce in MS is more frequent among ence of gender on employment for MS patients.
men or women. Three studies described similar Some studies have reported that gender has no
marital and relationship habits among both gen‑ effect [291,292] , while others found that men are
ders [278,283,284] . Glantz et al. followed a cohort more likely to be employed [284,293–295] . Hakim
of 108 MS patients married at the time of diag‑ et al. reported that most patients who change
nosis, for 5 years: the woman was the affected their employment status from full-time to part-
partner in 96% of the 23 divorces observed [285] . time are women [296] . This could be explained
Harrison et al. investigated the different ben‑ by the more frequent progressive course for men,
efits that women and men with MS could get from which does not allow such a change. However,
marriage [286] . They observed that for men being another study failed to report this difference [291] .
married was associated with a better acceptance of Rumrill et al. assessed discrimination at work
disability and less perceived impairment. towards men and women with MS [295] . They
According to McCabe et al., relationship satis‑ found both genders were victims of discrimina‑
faction was similar for men and women with MS tion related to discharge and reasonable accom‑
and correlated with sexual activity and sexual modations, but women were more frequently
satisfaction for both, although this association reported harassment and men alleged more hiring
was stronger for women than for men [283,287] . and reinstatement discrimination.
The same author observed that cognitive func‑
tioning, quality of sleep and rest predicted the Financial problems
relationship quality for women [283] . In a study from Hakim et al. financial problems
related to MS were reported by 46% of men,
Sexuality & sexual dysfunction compared with 26% of women [296] .
Sexual dysfunction is a prevalent and major symp‑
tom in MS that severely affects QoL. Its evalu‑ Health maintenance
ation requires insight into the primary changes The prior review by Coyle indicated that health
that directly affect libido (i.e., sexual response and maintenance was often neglected in MS patients,
orgasm due to direct damage to the nervous sys‑ and proposed a preventive healthcare plan [1] .
tem); the secondary changes (i.e., complaints that
are related to the physical disability of MS, such Healthcare costs
as fatigue, muscle rigidity, weakness and spasms); An American study found that cost for healthcare
and the tertiary changes (emotional, social and utilization in MS was affected by gender. Men with
cultural) aspects of MS. The components of MS had higher annual medical charges in com‑
MS-associated sexual dysfunction are reviewed parison with healthy men, but this was not the case
in [288] . for women, who already have higher healthcare
costs when healthy [297] . This is the only study that
Impact of MS on the caregiver analyzed the gender effect specifically. In other
Certain characteristics of MS burden differentially studies, healthcare cost increased with disease pro‑
affect satisfaction with life, based on the gender gression and with use of disease-modifying drugs,
of the caregiver. Increasing severity of disability, without gender influence [298] .
and duration of caregiving have a stronger adverse
effect on women. Surprisingly, the authors found Self-assessment of health & QoL
a positive correlation between duration of illness A recent abstract reviewed self-rated health
and satisfaction with life for male caregivers, status in MS patients by means of the SF-36

questionnaire (eight studies), and acknowl‑ someone will or will not have MS. Gene therapy,
edged similar results for men and women [299] ; given the number of genes involved and their
this is concordant with others studies [300–306] . small contribution, is unlikely to ever be possible.
A few studies report that women [298,307–309] or Pregnancies can now be envisaged with a realistic
men [310–313] have a better QoL. Casetta et al. optimism. Withholding DMTs is counterbal‑
observed a marked reduction in QoL as the anced by the decrease in disease activity during
EDSS increases for men, while the correlation pregnancy. Postpartum relapses are generally
was less striking for women, especially after an mild; breastfeeding may have a protective effect
EDSS of 5 [309] . in this regard. The uncovering of the mecha‑
nisms underpinning the frequent cognitive prob‑
End of life lems will help in keeping patients personally and
Multiple sclerosis rarely culminates in early socially active. Understanding the impacts of a
death. Occasionally, the patient ends up in a chronic illness such as MS will help patients and
chronic care institution in a vegetative state, their families in coping with its often devastating
sometimes for years, with no hope of recov‑ effects. The increased attention MS has received
ering any kind of autonomy. To avoid these in the last 3 decades will help in attaining a long
situations, it is advisable to have open discus‑ awaited cure.
sions, in appropriate circumstances, about the
degree of intervention wished by the individual, Future perspective
should severe, irreversible worsening occur. Advances in immunology, genetics, neurobiology
Most patients are willing to consider autopsy and their interconnections with the endocrine sys‑
for scientific purposes. tem, coupled with the refinement of epidemiolog‑
Assisted suicide is legalized in some European ical methods, should lead to explanations for the
countries (e.g., The Netherlands, Switzerland tremendous increase in MS susceptibility among
and Belgium). A Swiss group has reported women. Meanwhile, a better understanding of
on 421 assisted suicides over a 3-year period. the different impacts of MS on women and men
They report an increased proportion of younger will help in tailoring treatments; in this regard,
patients and of women. They offer no other female and male hormones may become part of
explanation, than to say that women are more the treatment strategies. Pregnancy will become
expressive of their feelings than men [314] . better integrated in the life course of women
with MS, as the impact of breastfeeding is better
Conclusion defined. A prospective pregnancy register for MS,
Research in neurobiology, immunology and currently in the planning stages, could generate
endocrinology is converging. Many of the key needed data on the influence of treatments of MS
molecules in one system are known to play on the course and outcome of pregnancies.
important roles in the other systems. Molecules
can assume different roles according to the Financial & competing interests disclosure
milieu. As we better understand the cross-talk Pierre Duquette has served on advisory boards, given lectures,
between these systems, we will be in a better run clinical trials, received research support and financial
position to unravel the etiopathogenesis of many support to attend meetings from the following companies:
common diseases, such as MS. Bayer-Schering, Biogen-Idec, EMD Serono, Novartis, TEVA
We have updated a previous review of gender Neuroscience. Pierre Duquette is funded by the following
issues in MS. In addition to the increasing sus‑ peer-reviewed agencies: Canadian Institutes for Health
ceptibility of women to MS, the complexities of Research, Multiple Sclerosis Society of Canada. Patricia K
the interaction between the nervous, genetic and Coyle has received honoraria for teaching and educational
immune systems are increasingly understood. activities from Acorda, Bayer, Biogen-Idec, EMD Serono,
These advances will contribute to more rational Novartis, Pfizer, Sanofi Aventis and Teva Neurosciences, and
treatments of the disease. Sex hormones might current funding from Novartis and Sanofi Aventis. Céline
have a role in neuroprotective and restorative Jobin has received honoraria for educational activities from
therapies. Although deficiencies in vitamin D are Teva, Biogen-Idec and EMD Serono. The authors have no
well documented, it is not yet known whether other relevant affiliations or financial involvement with any
their correction would be beneficial. A preventive organization or entity with a financial interest in or financial
trial with vitamin D in at-risk populations would conflict with the subject matter or materials discussed in the
be worthwhile, but results would be accrued only manuscript apart from those disclosed.
after long time periods. With the current state No writing assistance was utilized in the production of
of knowledge, it is impossible to predict whether this manuscript.

Executive summary
Incidence & prevalence
• The incidence and prevalence of multiple sclerosis (MS) has increased over the last decades, with a disproportionate increase in
women, especially in countries with a high basic prevalence in MS. Unraveling the mechanisms underlying this conspicuous finding will
help in finding the cause(s) of MS.
Sex hormones & immunity
• Sex hormones have an increasingly recognized role in the development of the CNS and immune system. The importance of cross-talk
between the hormonal, nervous and immune systems is being addressed.
• Estrogens and testosterone have protective effects on the nervous tissue. They are currently undergoing testing in therapeutic trials in
MS patients.
• Leptin, a hormone produced by adipocytes, has an anti-inflammatory effect on the immune response; it could have a
therapeutic potential.
Genetic aspects
• Several MS susceptibility genes have been identified, the most important ones being part of the MHC; others are involved in the
immune response. All have a small effect on susceptibility, but could be important in uncovering new therapeutic avenues.
Latitude & vitamin D
• Vitamin D could explain the latitudinal gradient observed in the prevalence of MS. Vitamin D supplementation may possibly have a
protective effect on MS susceptibility and course.
Clinical aspects
• There are some differences between women and men in disease course, prognosis, MRI and response to treatment.
Pregnancy & MS
• Pregnancy is now encouraged in women with MS, when circumstances are favorable. The frequency of relapses decreases in the last
two trimesters of pregnancy, with a brief surge of relapses during the postpartum first trimester.
• Some data indicate that breastfeeding has a protective effect on MS course. This could be related to a beneficial effect of prolactin on
myelin repair.
Psychosocial aspects
• Depression is frequent in MS, especially among women. Patients and caregivers need help in dealing with emotional problems. End of
life issues must be addressed adequately to avoid undue stress.
6. Orton SM, Ramagopalan SV, 12. Sarasoja T, Wikstrom J, Paltamaa J,

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Review

Gender issues in multiple sclerosis:

1929. This increase has been attributed in large Latitudinal gradient

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of the brain. One example of this is the expres‑

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allergic encephalomyelitis (EAE)/MS patho‑ electrophysiologic function in neurons, protect

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Table 1. Considerations for parenthood in patients with multiple sclerosis.

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Recurrence risk (%)

Age at disease onset 0

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Table 2. Gender differences in brain volumes in patients with multiple sclerosis.

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Effect of MS on the baby symptoms. The incidence of MS was found to be

Table 3. Evolution of multiple sclerosis symptoms with menopause.

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6. Orton SM, Ramagopalan SV, 12. Sarasoja T, Wikstrom J, Paltamaa J,

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