Background
Multiple sclerosis (MS) disproportionately affects females, with prevalence more than three times higher than in males. Despite this marked sex difference, relatively little is known about how reproductive hormones, such as oestrogen and progesterone, modulate disease symptoms. While pregnancy and menopause have been explored in the context of MS, the influence of the menstrual cycle on symptom burden remains poorly understood. Individuals with MS experience variable symptoms including fatigue, weakness, and impaired balance or coordination, which some evidence suggests may worsen during low-hormone phases of the cycle (Schwendimann & Alekseeva, 2007; Zorgdrager & de Keyser, 1997). However, a detailed mechanistic explanation of these symptom fluctuations has yet to be established.
Recent work from our group has shown that in healthy females, variations in oestrogen and progesterone across the menstrual cycle modulate motor system excitability. Elevated hormone concentrations around mid-cycle enhance corticospinal excitability, facilitating neural drive to muscle (Piasecki et al., 2024). Conversely, during low-hormone phases, reduced excitability may impair motor control. In MS, reduced corticospinal excitability and impaired intracortical neurotransmission have been linked to greater fatigue and disability (Coates et al., 2020; Conte et al., 2009). Understanding whether hormone-related modulation of motor pathways contributes to symptom variability in MS could therefore inform new approaches to symptom management.
Aims and Objectives
This study aims to (1) provide a comprehensive neurophysiological characterisation of the brain-to-muscle pathway across the menstrual cycle in individuals with MS, and (2) determine how fluctuations in reproductive hormones influence both functional tasks and symptom experience , with the goal of informing tailored therapeutic and self-management strategies.
Methods
Fifty-four individuals with MS (18 naturally menstruating females, 18 hormonal contraceptive users, 18 males) aged 18-40 years will be recruited. Naturally menstruating participants will attend three laboratory sessions corresponding to distinct hormonal timepoints, verified through serum sample hormone assays. Hormonal contraceptive users and male participants will complete matched sessions across comparable time intervals to control for repeated-measures effects.
At each visit, participants will complete validated questionnaires assessing fatigue, mood, and quality of life, alongside functional motor tests evaluating gait, balance, and manual dexterity. Neurophysiological assessments will include transcranial magnetic stimulation (TMS) to quantify corticospinal excitability and intracortical inhibitory and facilitatory neurotransmission, as well as high-density surface electromyography (HD-sEMG) of the tibialis anterior muscle to characterise motor unit behaviour during voluntary contractions. Data will be analysed to determine phase-related changes in corticospinal and motoneuronal underpinnings of motor function, and their associations with symptom severity.
Significance
This study will be the first to investigate how menstrual cycle-related hormonal fluctuations influence corticospinal and motor unit function in individuals with MS. By integrating neurophysiological and functional assessments, it aims to uncover mechanistic links between reproductive hormones and symptom variability. The findings will provide critical insight into the timing and physiological basis of symptom exacerbations, supporting the development of evidence-based strategies for optimising function, treatment timing, and quality of life in females with MS.