Patricia K. Coyle, MD, FAAN, FANA

Multiple sclerosis (MS) is a major central nervous system (CNS) inflammatory and demyelinating disorder. It typically affects young adults. Disease etiology involves genetics, environmental factors, and an immune system attack on the CNS. Biological sex differences permeate MS, and the hope has been that studying sex differences will provide important pathogenic and therapeutic insights.

 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

Multiple sclerosis (MS) is a major central nervous system (CNS) inflammatory and demyelinating disorder. It typically affects young adults. Disease etiology involves genetics, environmental factors, and an immune system attack on the CNS. Biological sex differences permeate MS, and the hope has been that studying sex differences will provide important pathogenic and therapeutic insights.

 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

Multiple sclerosis (MS) is a major central nervous system (CNS) inflammatory and demyelinating disorder. It typically affects young adults. Disease etiology involves genetics, environmental factors, and an immune system attack on the CNS. Biological sex differences permeate MS, and the hope has been that studying sex differences will provide important pathogenic and therapeutic insights.

 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults.