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Background: Only few studies have monitored the potential of physical activity training and physical therapy to modulate the reaction of the endocrine system. In this study, the effect of neuroproprioceptive facilitation and inhibition physical therapy on clinical outcomes and neuroactive steroids production in people with multiple sclerosis was evaluated. Moreover, we were interested in the factors that influence the treatment effect. Methods: In total, 44 patients with multiple sclerosis were randomly divided into two groups. Each group underwent a different kind of two months ambulatory therapy (Motor program activating therapy and Vojta’s reflex locomotion). During the following two months, participants were asked to continue the autotherapy. Primary (serum level of cortisol, cortisone, 7α-OH-DHEA, 7β-OH-DHEA, 7-oxo-DHEA, DHEA) and secondary (balance, cognition and patient-reported outcomes) outcomes were examined three times (pre, post, and washout assessments). Results: In both groups, there is a decreasing trend of 7-oxo-DHEA concentration in post-assessment and 7β-OH-DHEA in washout versus pre-assessment. A higher impact on neuroactive steroids is visible after Vojta’s reflex locomotion. As for clinical outcomes, the Paced Auditory Serial Addition Test and Multiple Sclerosis Impact Scale significantly improved between post-assessment and washout assessment. The improvement was similar for both treatments. Conclusions: Neuroproprioceptive facilitation and inhibition improved the clinical outcomes and led to non-significant changes in neuroactive steroids. Trial registration (NCT04379193).

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