Measuring MS Symptoms in Relation to Menstrual Cycles: Exploring How MS Symptoms May be Affected at Different Times During a Menstrual Cycle in Females Living With Multiple Sclerosis
Conditions: Multiple Sclerosis, Menstrual Cycle
Sponsor: University of Alberta

Protocol Version: 05-March-2025 
Title: My MS and My Menstrual Cycle 
Measuring MS symptoms in relation to menstrual cycles:  exploring how MS symptoms 
may be affected at different times during a menstrual cycle in females living with 
Multiple Sclerosis 
Research Team:  
Smyth P, Brennand EA, McCombe J, Wilbur C, Kate M, Swelin A, Kelly D, Richer L, 
Prociuk M, Ferrara G, Morrow SA. 
Objective: 
To evaluate the severity and timing of MS symptoms with timing of menstrual cycles in 
women living with MS. 
Methods:  
Design:  
This project is a prospective observational study of females living with MS, tracking MS 
symptoms in correlation with time of menstrual cycle, measured and correlated via a 
smartphone app  
Inclusion Criteria:  
Participants are required to meet the following criteria: 
● Females with diagnosed MS by 2024 McDonald Diagnostic criteria 1 (biologically 
sex-based, any gender as long as not on hormonal gender-enhancing therapy)  
● ages 16+, still experiencing menstruation with cycles of 23 to 36 days spacing  
● have entered menarche, are experiencing menstrual cycles, and have not yet 
entered menopause 
● participants may utilize hormonal contraceptive methods, such as oral 
contraceptive methods or hormonal IUDs 
● English-speaking 
● Willing to provide informed consent,  mature minors will provide informed consent, 
their physician will determine whether their level of maturity is appropriate to 
participate in the study and complete consent as a mature minor  
● Have the ability to complete questionnaires and operate the app  
 
Exclusion Criteria:  
People will be excluded as per the following criteria: 

Protocol Version: 05-March-2025 
● diagnosed with CNS inflammation disorders other than MS such as:  
o NMOSD (Neuromyelitis Optica Spectrum Disorder)  
o MOGAD (Myelin Oligodendrocyte Glycoprotein Antibody-associated 
Disease)  
● male or intersex individuals, given the inclusion criteria of requiring a uterus 
● females < 15 years of age  
● females who have not started menstruation 
● females who have stopped menstruation due to menopause or hysterectomy 
● pregnant or postpartum women < 1 year after delivery and/or people who 
currently breastfeeding 
● are unable to provide informed consent, or are not deemed a mature minor to 
complete consent are unable to complete questionnaires and operate the app  
 
Recruitment:  
Via treating neurologists (MS clinic or community-based) and/or nurse practitioners; 
flyers sent through social media newsletters MS Canada and MS research portal via MS 
Canada and in clinic rooms/waiting rooms neurologists’ practices; mass secure patient 
messaging via connectcare electronic medical records system 
Randomization:   
n/a 
Intervention:  
Eligible patients will download the My Normative app, by scanning a link/QR code.  
Once registered, electronic consent will be collected through the app. Participants will fill 
out a baseline series of demographics in addition to a series of patient-reported 
outcome measures (fatigue, patient perceived level of disability, MS patient symptoms 
screen, sleep, self-efficacy scale, self-perceived cognition and coping levels, motivation 
for cognition, and depression and anxiety levels) on the app, as well as enter 
information re:  menstrual cycle tracking/hormone levels as prompted by the app. 
Participants will then track their menstrual cycles for 6 months with completion of patient 
reported outcome measures:  (1) fatigue – MFIS – 5 item;2-4 (2) depression & anxiety - 
HADS;5 (3) coping (mini-COPE); (4) MFC – motivation for cognition,6 (5) 
MSymptoscreen (screen of common MS symptoms)7 and likert scale from 0 to 7 as to 
self-perceived cognition levels. This will be done five times per month, as per the 
different phases of the menstrual cycle. At the end of 6 months, participants will 
complete an exit scale – with all of the above.  
 

Protocol Version: 05-March-2025 
Duration of Study Involvement:  
6 months (this has been determined to be optimal in capturing 3 months of menstrual 
cycles) 
This study will be a 2 year study with rolling enrollment 
Primary outcomes:  
Difference in modified MFIS (fatigue) levels, 5 items during menstruation compared to 
other times of the menstrual cycle 3, 4, 8-10. 
Secondary outcomes: 
Qualitative self-reported difference:  
● HADS (Hospital anxiety and depression scale) – 14 items 5  
● MNSQ (Multiple Sclerosis Neuropsychological Screening Questionnaire–Patient 
Version) - 15 items 10-13 
● Two Likert scale – self perceived cognition levels (0 to 7) 
● Coping – MS specific – Brief COPE Short Version (Mini-Cope) – 12 items (3 
different coping styles:  active/adaptive, avoidant/maladaptive, and 
emotional/neutral 14  
● MFC scale (motivation for cognition)6 
● the SymptoMScreen - 12 item (walking, hand function/dexterity, spasticity & 
stiffness, bodily pain, sensory symptoms, bladder control, fatigue, vision, 
dizziness, cognition function, depression, anxiety), (Green et al Applied 
Neuropsych 2016) 
Sample size:  
We plan to recruit a convenience sample over 2 years, with a maximum of 300 
participants. There are no substantial prior studies to base the sample size calculation 
upon. 
 
Hypothesis:  
Women with MS experience worsening fatigue, as self-reported by MFIS, during 
menstruation compared to other times during their menstrual cycles.  
 
1.0 Background and Rationale: 
 
MS most commonly occurs in young adults and persists lifelong.15, 16 It is associated 
with a number of physical symptoms such as numbness, weakness, troubles with 
balance, walking, and vision. However, invisible symptoms of MS are often more 
debilitating, such as fatigue and cognition (brain fog).17 MS is more common in women 

Protocol Version: 05-March-2025 
compared to men, preferentially increasing in women over time as compared to men.18-
21.  
 
There are unique features of multiple sclerosis in women:  the course of MS appears to 
be associated with a number of female-specific features, such as onset in women more 
after menarche;22 less inflammatory activity of MS during pregnancy, and increase in 
the first 3 to 6 months postpartum.23, 24 Furthermore, exclusive breastfeeding is thought 
to be slightly neuroprotective in MS.25-28 Animal model studies suggested an association 
between female sex hormones in pregnancy and effects on MS inflammation.29 
Therefore, researchers have wondered about the effects of female hormones on the 
course of MS, with suggested impact upon MRI activity in women living with MS.30-34 
However, it is controversial as to how and whether female hormones impact MS activity, 
symptoms of MS, progression of MS.35, 36 Two randomized controlled trials of 
pregnancy-related sex hormones in women with relapsing remitting MS were 
negative.23, 29, 37-39 Despite the lack of definitive association, women with MS have 
reported fluctuations of MS symptom severity over their menstrual cycles.40, 41 
 
A recent prospective study examining MS symptom severity variability at points 
throughout women’s menstrual cycle was published in 2023; participants reported a 
number of symptoms at different points during their menstrual cycles and there was a 
suggestion of less fatigue as measured by the MFIS during the perimenstrual period as 
compared to the luteal period, not felt to be clinically significant, as well as less 
variability in fatigue reported by women on continuous hormonal oral contraception 
compared to those who weren’t. The authors conclude that more studies are needed to 
examine the possible relationship between menstruation and MS symptoms.42 
 
The My Normative platform app has been used in other populations to track menstrual 
cycles in relation to various symptoms for women in the general population and other 
conditions.(mynormative.ca) We hope to examine MS-related symptoms to stages of 
the menstrual cycle, as measured by the My Normative platform.(mynormative.ca) We 
hypothesize that MS-related fatigue would be greater in the luteal phase of the cycle as 
compared to other times of women’s menstrual cycles, as measured by the MFIS-5 
item.3 Secondary outcomes will include impact of menstrual cycle stage upon cognition 
as measured by the likert scale of self-perceived cognitive levels from 1 to 7, various 
MS symptoms as measured by the SymptoMScreen (walking, hand function/dexterity, 
spasticity & stiffness, bodily pain, sensory symptoms, bladder control, fatigue, vision, 
dizziness, cognition function, depression, anxiety),7 MFC scale (motivation for 
cognition)6 and coping (the mini-cope)14 over a 6 month period with a minimum of 3 
months of menstrual cycle tracking. The My Normative platform tracks menstrual cycles 
in five phases:  (1) menstrual phase; (2) follicular phase; (3) ovulation phase; (4) Luteal 
phase early; (5) luteal phase late 

Protocol Version: 05-March-2025 
2.0 Proposed Research  
Hypothesis:  
Women with MS experience worsening of fatigue, as self-reported by MFIS, during 
menstruation compared to other times during their menstrual cycles.  
Design: 
Prospective observational self-enrolled study on mobile app. 
Setting:  
online, app reporting 
Subjects: 
Females living with MS, who experience menstruation. 
Inclusion Criteria:  
Participants are required to meet the following criteria: 
● Females with diagnosed MS by 2017 McDonald criteria 1 (biologically sex-based, 
any gender as long as not on hormonal gender-enhancing therapy)  
● ages 16+, still experiencing menstruation with cycles of 23 to 36 days spacing  
● have entered menarche, are experiencing menstrual cycles, and have not yet 
entered menopause 
● participants may utilize hormonal contraceptive methods, such as oral 
contraceptive methods or hormonal IUDs 
● English-speaking 
● Willing to provide informed consent,  mature minors will provide informed consent, 
their physician will determine whether their level of maturity is appropriate to 
participate in the study and complete consent as a mature minor  
● Have the ability to complete questionnaires and operate the app  
 
Exclusion Criteria:  
People will be excluded as per the following criteria: 
● diagnosed with other CNS inflammation disorders than MS 
● male or intersex individuals, given the inclusion criteria of requiring a uterus 
● females < 15 years of age  
● females who have not started menstruation 
● females who have stopped menstruation due to menopause or hysterectomy 

Protocol Version: 05-March-2025 
● pregnant or postpartum women x 1 year after delivery and/or people who 
currently breastfeeding 
● are unable to provide informed consent 
● are unable to complete questionnaires and operate the app 
Randomization:   
n/a 
Questionnaires: 
Baseline: 
● PDDS – single scale (physical disability measure) Patient Determined Disease 
Steps 43  
● Full MFIS – Modified Fatigue Impact Scale (21 point scale) – fatigue 2, 8, 9  
● HADS (anxiety & depression) – Hospital Anxiety & Depression Scale (14 items)5  
● PHQ9 – Patient Health Questionnaire (depression & anxiety) (9 items)44, 45  
● MSNQ (cognition) (15 item)11-13  
● Mini Cope (coping) (12 item)46 
● Pittsburgh sleep quality index (sleep quality) (24 items)47  
● the SymptoMScreen (12 item) (walking, hand function/dexterity, spasticity & 
stiffness, bodily pain, sensory symptoms, bladder control, fatigue, vision, 
dizziness, cognition function, depression, anxiety)7, 42  
● MFC scale (Motivation for Cognition) (10 item)6  
● General factors 
o Demographics (age, race, ethnicity, marital status, level of education, # 
children, working outside/inside home), BMI, smoking status  
o Years since onset MS (first symptoms) and diagnosis 
o Disease modifying therapies list 
o Medications listt 
● Menstrual cycle information 
o Length of cycle 
● Type of contraception 
o Rhythm method 
o No contraception 
o Barrier  
▪ Condoms 
▪ Diaphragm 
o IUD (with hormone, without hormone) 

Protocol Version: 05-March-2025 
o OCP – type – continuous/not continuous 
 
● 5 time points during the menstrual cycle  
1) Follicular phase, during active menstruation 
2) Follicular phase, no menstruation (leading up to ovulation) 
3) ovulation phase 
4) Luteal phase, first half 
5) Luteal phase, second half (this is the 5-7 days before the next period 
starts) 
Each time point: 
● MFIS brief 5 item 3  
● Cognition Likert scale – self perceived cognition levels (0-7) 
● SymptoMSScreen 12 item 7  
● Mini-COPE (12 item)14  
● MFC scale (motivation for cognition) 10 item6  
● Longer MFIS point scale once per cycle, alternating timing of long scale done at 
each time point (3 points within cycle) over study duration (6 months) 2, 8, 9 
Study Completion: 
● PDDS – single scale (physical disability measure) Patient Determined Disease 
Steps43  
● Full MFIS – modified fatigue Impact Scale (21 point scale) – fatigue2, 8, 9  
● HADS (anxiety & depression) – Hospital Anxiety & Depression Scale – 14 items 5  
● PHQ9 – patient health questionnaire (depression & anxiety) – 9 items 44, 45  
● MSNQ (cognition) 15 item 11-13  
● Cognition Likert scale – self-perceived cognition levels (0 – 7) 
● Mini Cope (coping) (12 item) 46 
● Pittsburgh sleep quality index (sleep quality) 24 items 47 
● the SymptoMScreen - 12 item (walking, hand function/dexterity, spasticity & 
stiffness, bodily pain, sensory symptoms, bladder control, fatigue, vision, 
dizziness, cognition function, depression, anxiety) 7  
● MFC scale (motivation for cognition) – 10 item 6  
● Relapses in past 6 months/use of steroids 
● Optional - agreement to be contacted to participate in qualitative interview re: use 
of app 
Sample size: 
There is not much information or data to calculate sample size. We plan to recruit 300 
women living with MS for this study as a convenience/availability sample from the two 

Protocol Version: 05-March-2025 
MS Clinics at the University of Alberta and University of Calgary (approximately 150 per 
site). 
 
Taylor et al completed a pilot study, published in 2023, on menstrual cycle and fatigue 
symptoms in eumenorrheic women living with MS. There was a suggestion of less 
fatigue in the perimenstrual period compared to the luteal portion of the cycle, and less 
fluctuation in symptom severity over the cycle for women on continuous hormonal oral 
contraception. There was a lot of difficulty recruiting for this study with over 200 women 
contacted and 70 enrolled and 47 providing more than 4 weeks of data for a 6 month 
period. 42 Despite the challenges faced by these authors, and anticipating a 20% 
dropout, we plan to try to recruit a maximum of 300 participants over 2 years. There are 
no substantial prior studies to base the sample size calculation upon. 
 
Analytical Plan:   
We will calculate summary statistics for primary and secondary outcomes across 
different menstrual cycle phases. We will conduct hypothesis tests (e.g., t-tests, 
ANOVA) to determine if there are statistically significant crude differences in MS 
symptom severity or relapse rates among different menstrual cycle phases and explore 
the relationship between the timing of the menstrual cycle and MS symptom severity 
using correlation coefficients (e.g., Pearson's correlation). We will perform regression 
analysis to identify any potential predictors of MS symptom severity, including menstrual 
cycle phase, age, duration of MS, and other relevant covariates and stratify the analysis 
by age groups to explore for effect modification by reproductive stage of youth, early 
adulthood (reproductive years) and later adulthood (peri-menopause), respectively 
defined as participants < 20 years old, 20 to 40 years old, > 40 years old. We will control 
for potential confounding variables, such as medication use, comorbidities, and lifestyle 
factors, in these adjusted models. Finally, we will perform sensitivity analysis to assess 
the robustness of the results by varying assumptions or analytical methods. Finally, we 
will provide descriptive measures of baseline characteristics/demographics.  
Feasibility:   
This study will be carried out through the reciprocal ethics process at the Universities of 
Alberta and Calgary. Each MS Clinic at each clinic follows about 5000 PwMS in Alberta. 
MS affects 3 women to every man, with average onset between ages 20 to 40. 
Therefore, both clinics see many women with MS who are at ages who experience 
menarche.  
Timelines:   
2 years, each site to recruit 150 participants maximum 
What this study adds:   
Despite the longstanding knowledge of MS risk, onset, and inflammatory activity being 
related to different hormonal periods throughout women’s lives, there is still much that is 
unknown about the interactions and relationship of female hormones and different 

Protocol Version: 05-March-2025 
female hormonal states upon MS. In addition, women with MS often report MS 
symptoms as fluctuating in severity at different points throughout their menstrual cycles. 
However, despite reporting, literature has not shown definitive correlations between MS 
symptom severity in relation to different points in the menstrual cycle. If we are able to 
establish correlations between common MS symptoms at particular points in the 
menstrual cycle, this will aid researchers, clinicians, and women living with MS around 
examining different strategies to try to treat MS symptom severity at different points 
throughout the menstrual cycle. This could include strategies such as that seen with 
perimenstrual migraine, where women enact prophylactic strategies around the time of 
menstruation to minimize their migraine headaches during that time of the cycle. 48 
 
Methodologic Issues: 
Patients will self-enroll in the study, through accessing and downloading the app as per 
instruction. Participants download the My Normative App and become a registered user.  
Once registered, they will read the consent and then sign consent if they wish to 
participate in the study. Participants will have the option of withdrawing from the study at 
any time by simply not responding to cues from the app to fill out their questionnaires.   
Participants are provided with contact information for the study team, and can withdraw 
from the study by contacting the study team. 
 
 
 
 
 
 
 
 
 
References:   
 
1. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 
revisions of the McDonald criteria. Lancet Neurol 2018; 17: 162-173. 20171221. 
DOI: 10.1016/S1474-4422(17)30470-2. 
2. Cohen ET, Matsuda PN, Fritz NE, et al. Self-Report Measures of Fatigue for 
People With Multiple Sclerosis: A Systematic Review. J Neurol Phys Ther 2024; 
48: 6-14. 20230704. DOI: 10.1097/NPT.0000000000000452. 
3. Cozart JS, Strober L, Ruppen S, et al. A quick assessment of reliable change in 
fatigue: Reliable change indices of the modified fatigue impact scale - 5 item 
(MFIS-5). Mult Scler Relat Disord 2021; 49: 102743. 20210107. DOI: 
10.1016/j.msard.2021.102743. 

Protocol Version: 05-March-2025 
4. Smith J, Bruce AS, Glusman M, et al. Determining reliable change on the 
modified fatigue impact scale (5-item version). Mult Scler Relat Disord 2018; 20: 
22-24. 20171214. DOI: 10.1016/j.msard.2017.12.008. 
5. Honarmand K and Feinstein A. Validation of the Hospital Anxiety and Depression 
Scale for use with multiple sclerosis patients. Mult Scler 2009; 15: 1518-1524. 
20091113. DOI: 10.1177/1352458509347150. 
6. Blaise M, Marksteiner T, Krispenz A and Bertrams A. Measuring Motivation for 
Cognitive Effort as State. Front Psychol 2021; 12: 785094. 20211209. DOI: 
10.3389/fpsyg.2021.785094. 
7. Green R, Kalina J, Ford R, et al. SymptoMScreen: A Tool for Rapid Assessment 
of Symptom Severity in MS Across Multiple Domains. Appl Neuropsychol Adult 
2017; 24: 183-189. 20160414. DOI: 10.1080/23279095.2015.1125905. 
8. Fisk JD, Pontefract A, Ritvo PG, et al. The impact of fatigue on patients with 
multiple sclerosis. Can J Neurol Sci 1994; 21: 9-14. 
9. Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial 
validation of the fatigue impact scale. Clin Infect Dis 1994; 18 Suppl 1: S79-83. 
DOI: 10.1093/clinids/18.supplement_1.s79. 
10. Van Laethem D, De Cock A, Van Schependom J, et al. Correlates of patient-
reported cognitive performance with regard to disability. Sci Rep 2022; 12: 
13489. 20220805. DOI: 10.1038/s41598-022-17649-3. 
11. Benedict RH, Munschauer F, Linn R, et al. Screening for multiple sclerosis 
cognitive impairment using a self-administered 15-item questionnaire. Mult Scler 
2003; 9: 95-101. DOI: 10.1191/1352458503ms861oa. 
12. Kim S, Zemon V, Rath JF, et al. Screening Instruments for the Early Detection of 
Cognitive Impairment in Patients with Multiple Sclerosis. Int J MS Care 2017; 19: 
1-10. DOI: 10.7224/1537-2073.2015-001. 
13. O'Brien A, Gaudino-Goering E, Shawaryn M, et al. Relationship of the Multiple 
Sclerosis Neuropsychological Questionnaire (MSNQ) to functional, emotional, 
and neuropsychological outcomes. Arch Clin Neuropsychol 2007; 22: 933-948. 
20070911. DOI: 10.1016/j.acn.2007.07.002. 
14. Brambila-Tapia AJL, Martinez-Arriaga RJ, Gonzalez-Cantero JO, et al. Brief 
COPE Short Version (Mini-COPE): A Proposal of Item and Factorial Reduction in 
Mexican Population. Healthcare (Basel) 2023; 11 20230408. DOI: 
10.3390/healthcare11081070. 
15. Browne P, Chandraratna D, Angood C, et al. Atlas of Multiple Sclerosis 2013: A 
growing global problem with widespread inequity. Neurology 2014; 83: 1022-
1024. DOI: 10.1212/WNL.0000000000000768. 
16. Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis 
worldwide: Insights from the Atlas of MS, third edition. Mult Scler 2020; 26: 1816-
1821. 20201111. DOI: 10.1177/1352458520970841. 
17. Oh J, Vidal-Jordana A and Montalban X. Multiple sclerosis: clinical aspects. Curr 
Opin Neurol 2018; 31: 752-759. DOI: 10.1097/WCO.0000000000000622. 
18. Bove R. Women's Issues in Multiple Sclerosis. Semin Neurol 2016; 36: 154-162. 
20160426. DOI: 10.1055/s-0036-1579736. 
19. Harbo HF, Gold R and Tintore M. Sex and gender issues in multiple sclerosis. 
Ther Adv Neurol Disord 2013; 6: 237-248. DOI: 10.1177/1756285613488434. 

Protocol Version: 05-March-2025 
20. Hauser SL and Oksenberg JR. The neurobiology of multiple sclerosis: genes, 
inflammation, and neurodegeneration. Neuron 2006; 52: 61-76. DOI: 
10.1016/j.neuron.2006.09.011. 
21. Koch-Henriksen N, Thygesen LC, Stenager E, et al. Incidence of MS has 
increased markedly over six decades in Denmark particularly with late onset and 
in women. Neurology 2018; 90: e1954-e1963. 20180502. DOI: 
10.1212/WNL.0000000000005612. 
22. Jiang X, Olsson T and Alfredsson L. Age at Menarche and Risk of Multiple 
Sclerosis: Current Progress From Epidemiological Investigations. Front Immunol 
2018; 9: 2600. 20181113. DOI: 10.3389/fimmu.2018.02600. 
23. Vukusic S, Hutchinson M, Hours M, et al. Pregnancy and multiple sclerosis (the 
PRIMS study): clinical predictors of post-partum relapse. Brain 2004; 127: 1353-
1360. 20040506. DOI: 10.1093/brain/awh152. 
24. Langer-Gould A, Smith JB, Albers KB, et al. Pregnancy-related relapses and 
breastfeeding in a contemporary multiple sclerosis cohort. Neurology 2020; 94: 
e1939-e1949. 20200413. DOI: 10.1212/WNL.0000000000009374. 
25. Hellwig K, Rockhoff M, Herbstritt S, et al. Exclusive Breastfeeding and the Effect 
on Postpartum Multiple Sclerosis Relapses. JAMA Neurol 2015; 72: 1132-1138. 
DOI: 10.1001/jamaneurol.2015.1806. 
26. Aigner S, Huhn K, Cepek L, et al. Breastfeeding in Mothers with Multiple 
Sclerosis: The German Experience. Breastfeed Med 2023; 18: 241-245. 
20230216. DOI: 10.1089/bfm.2022.0279. 
27. Collorone S, Kodali S and Toosy AT. The protective role of breastfeeding in 
multiple sclerosis: Latest evidence and practical considerations. Front Neurol 
2022; 13: 1090133. 20230124. DOI: 10.3389/fneur.2022.1090133. 
28. Langer-Gould A and Beaber BE. Effects of pregnancy and breastfeeding on the 
multiple sclerosis disease course. Clin Immunol 2013; 149: 244-250. 20130127. 
DOI: 10.1016/j.clim.2013.01.008. 
29. Voskuhl RR and Gold SM. Sex-related factors in multiple sclerosis susceptibility 
and progression. Nat Rev Neurol 2012; 8: 255-263. 20120327. DOI: 
10.1038/nrneurol.2012.43. 
30. El-Etr M, Vukusic S, Gignoux L, et al. Steroid hormones in multiple sclerosis. J 
Neurol Sci 2005; 233: 49-54. DOI: 10.1016/j.jns.2005.03.004. 
31. Patas K, Engler JB, Friese MA and Gold SM. Pregnancy and multiple sclerosis: 
feto-maternal immune cross talk and its implications for disease activity. J 
Reprod Immunol 2013; 97: 140-146. DOI: 10.1016/j.jri.2012.10.005. 
32. Sparaco M and Bonavita S. The role of sex hormones in women with multiple 
sclerosis: From puberty to assisted reproductive techniques. Front 
Neuroendocrinol 2021; 60: 100889. 20201112. DOI: 
10.1016/j.yfrne.2020.100889. 
33. Tintore M and Tur C. Understanding the role of gender and hormones in multiple 
sclerosis. Mult Scler 2014; 20: 518-519. DOI: 10.1177/1352458514528266. 
34. Ysrraelit MC and Correale J. Impact of sex hormones on immune function and 
multiple sclerosis development. Immunology 2019; 156: 9-22. 20181011. DOI: 
10.1111/imm.13004. 

Protocol Version: 05-March-2025 
35. Frohman TC, Beh SC, Kildebeck EJ, et al. Neurotherapeutic Strategies for 
Multiple Sclerosis. Neurol Clin 2016; 34: 483-523. DOI: 
10.1016/j.ncl.2016.05.001. 
36. Tomassini V and Pozzilli C. Sex hormones: a role in the control of multiple 
sclerosis? Expert Opin Pharmacother 2006; 7: 857-868. DOI: 
10.1517/14656566.7.7.857. 
37. Vukusic S, Ionescu I, Cornu C, et al. Oral nomegestrol acetate and transdermal 
17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The 
POPARTMUS study. Mult Scler 2021; 27: 1458-1463. 20201203. DOI: 
10.1177/1352458520978218. 
38. Vukusic S, Ionescu I, El-Etr M, et al. The Prevention of Post-Partum Relapses 
with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, 
objectives and state of advancement. J Neurol Sci 2009; 286: 114-118. 
20090915. DOI: 10.1016/j.jns.2009.08.056. 
39. Vukusic S and Marignier R. Multiple sclerosis and pregnancy in the 'treatment 
era'. Nat Rev Neurol 2015; 11: 280-289. 20150421. DOI: 
10.1038/nrneurol.2015.53. 
40. Zorgdrager A and De Keyser J. Menstrually related worsening of symptoms in 
multiple sclerosis. Journal of the neurological sciences 1997; 149: 95-97. 
41. Zorgdrager A and De Keyser J. The premenstrual period and exacerbations in 
multiple sclerosis. Eur Neurol 2002; 48: 204-206. DOI: 10.1159/000066166. 
42. Taylor H, Alhasan S, Saleem M, et al. Influence of menstrual cycle and hormonal 
contraceptive use on MS symptom fluctuations: A pilot study. Multiple sclerosis 
and related disorders 2023; 77: 104864. DOI: 
https://dx.doi.org/10.1016/j.msard.2023.104864. 
43. Learmonth YC, Motl RW, Sandroff BM, et al. Validation of patient determined 
disease steps (PDDS) scale scores in persons with multiple sclerosis. BMC 
Neurol 2013; 13: 37. 20130425. DOI: 10.1186/1471-2377-13-37. 
44. Beswick E, Quigley S, Macdonald P, et al. The Patient Health Questionnaire 
(PHQ-9) as a tool to screen for depression in people with multiple sclerosis: a 
cross-sectional validation study. BMC Psychol 2022; 10: 281. 20221128. DOI: 
10.1186/s40359-022-00949-8. 
45. Patrick S and Connick P. Psychometric properties of the PHQ-9 depression scale 
in people with multiple sclerosis: A systematic review. PLoS One 2019; 14: 
e0197943. 20190219. DOI: 10.1371/journal.pone.0197943. 
46. Carver CS. You want to measure coping but your protocol's too long: consider 
the brief COPE. Int J Behav Med 1997; 4: 92-100. DOI: 
10.1207/s15327558ijbm0401_6. 
47. Jerkovic A, Mikac U, Matijaca M, et al. Psychometric Properties of the Pittsburgh 
Sleep Quality Index (PSQI) in Patients with Multiple Sclerosis: Factor Structure, 
Reliability, Correlates, and Discrimination. J Clin Med 2022; 11 20220405. DOI: 
10.3390/jcm11072037. 
48. Vetvik KG and MacGregor EA. Menstrual migraine: a distinct disorder needing 
greater recognition. Lancet Neurol 2021; 20: 304-315. 20210215. DOI: 
10.1016/S1474-4422(20)30482-8.