Table 1.

Summary table of studies that examined the relationship between early menarche and MS risk. Studies including adult MS cases were limited to those who sampled age of puberty in at least 100 MS cases and controls. Pediatric studies that had smaller samples are included.

Study	Region	Type of study	Populations studied (N)	Puberty measurement	Findings
Operskalski et al. 1989 (21)	US	Case control Adult MS	MS Cases (145) Friend controls (145)	Age at menarche	–  Mean age of menarche in MS cases less than controls.
Ramagopalan et al. 2009 (8)	Canada	Case Control Adult MS	MS Cases (4472 F, 1,021 M) Spousal Controls (658 F, 1,101 M)	Information about at menarche, age of voice change, and pubarche collected by interview	– Mean age of menarche lower in female MS cases (12.4) compared to female controls (12.6) – Age at puberty not different between male MS cases and controls – There is a 10% reduction in the relative risk of MS for each year increase in age at puberty
Gustavsen et al. 2014 (22)	Norway	Case control Adult MS	MS cases from Oslo MS Registry (391 F, 139 M) Controls from Norwegian Bone marrow registry (535 F, 383 M)	Age at menarche information collected by questionnaire	– Mean age at menarche was not different in MS patients (13.1) compared to controls (13.0)
Chitnis et al. 2016 (5)	US	Case Control Pediatric MS	MS Cases (160 F, 94 M) Age, sex, and race-matched controls from same hospitals (206 F, 214 M)	Age at menarche, BMI, and pubertal staging data on both males and females collected at time of study visit.	– Age of menarche earlier in MS patients (11.6) compared to controls (11.9). – BMI higher in MS cases (76) vs. controls (63) – Among females, there is a correlation between higher BMI and younger age at menarche (this was not apparent not in boys) – There was an effect of BMI on MS risk only in post- but not pre-menarche girls (OR = 1.60). – Age of onset of symptoms occurred 0.91 years earlier for overweight females, particularly if they experienced puberty earlier.
Bove et al., 2016 (23)	US	Case control Adult MS	MS or CIS cases were white females from the CLIMB study (156) and 1,390 white women without MS but with a first-degree relative with MS from [Genes and Environment in Multiple Sclerosis (GEMS)].	Age at menarche and information about obesity in childhood (yes/no) collected by questionnaire	– Age at menarche similar between index cases (12.6) and controls (12.7). – Every year decrease in age at menarche was associated with a 0.65-year earlier MS onset
Rejali et al. 2016 (24)	Iran	Case control One Hospital Adult MS	MS Cases (200 F) Age-matched controls (200 F)	Assessment of age of onset of puberty was made by Tanner classification and age at menarche	– Age at menarche earlier in MS cases (13.0) compared to controls (13.5). – Inverse relationship between age of menarche and MS risk (OR = 0.78)
Nielsen et al. 2017 (26)	Denmark	Prospective Cohort Adult MS	Women enrolled in the Danish National Birth Cohort MS Cases (226 F) Controls (77 330 F)	Information about age at menarche was collected by interview at week 16 of pregnancy	– Mean age at menarche was earlier in female MS cases (13.0) compared to controls (13.3). – There was a 13% reduction in the relative risk of MS for each year increase in age at menarche. – Early menarche (<11 yo) is associated with 80% increased risk of MS, compared to late menarche (>15) (HR = 1.8). – Comparable hazard ratios seen after adjusting for co-variates
Salehi et al. 2018 (25)	Iran	Case control Adult MS	MS Cases (399 F) registered with Iranian MS society Controls (541 F)	Information about age at menarche collected by questionnaire	– Mean age of menarche in MS cases (13.14) was earlier than controls (13.36). – 1-year increase in age at menarche reduced MS risk by 10% (OR = 0.90)
Mirmosayyeb et al. 2018 (27)	Iran	Case control One hospital Adult MS	MS Cases (181 F, aged >14 years) Age-matched controls (202 F)	Information about age at menarche collected by interview.	– Mean age at menarche was not significantly different between MS cases (13.6) and controls (13.3) – MS cases did not exhibit higher body mass index than controls.
Belbasis et al., 2020 (17)	UK	Case Control Adult MS	MS Cases (1,381 F) Controls (229,197 F) UK Biobank	Age at menarche and body size at age 10 information collected at time of sample collection in Biobank	– Age at menarche earlier in MS cases (12.77) compared to controls (12.95). – One age later in menarche associated with protection from MS (OR = 0.93). – Having a higher-than-average body size at aged 10 also associated with higher risk of MS. – No significant association with age at which voice broke and age of first facial hair with risk of MS.
Zeydan et al. 2020 (28)	US	Case control Adult MS	MS Cases (137 F) Controls (396 F) were from the Mayo Clinical Cohort Study of Oophorectomy and Aging, and were matched with MS cases for year of birth.	Information about age at menarche collected by questionnaire and interview	– Mean age at menarche not different between MS cases (12.7) compared to controls (12.6).
Jacobs et al. 2021 (29)	UK	Case control Adult MS	MS Cases (1,635 F) Controls (263,058 F) UK Biobank	Information about age of menarche and body size at age 10 information collected from UK Biobank database.	– Earlier age at menarche and higher BMI associated with MS risk.