The Impact of Female Sex Hormones on Concussion

Abstract

The thesis aim was to understand the influence of female sex hormones on concussion via investigating: 1) How much does baseline symptomology change across the menstrual cycle in female athletes?; 2) Do salivary concussion biomarkers change across the menstrual cycle for females in the absence of injury?; 3) Does the hormone profile at point of injury predict prolonged recovery from a concussion?; 4) Does hormone profile at point of injury affect salivary concussion biomarkers in females? The thesis included a systematic review, a feasibility study, a cross-sectional study, a single-case study and a prospective cohort study. The systematic review and meta-analysis (chapter 2) highlighted sex and gender differences in sports-related injuries including a higher incidence of concussion in female athletes. Chapters 3 to 8 aimed to better understand concussion in females. In assessing concussion knowledge and attitudes (Chapter 3) via an online survey, over 30% of male and female football players indicated they would continue playing whilst experiencing symptoms of a concussion. This suggested that the observed gender difference in concussion incidence is unlikely to be only due to a reporting bias in females. Investigating the magnitude of change in self-report symptoms across the menstrual cycle (chapter 4) in the absence of injury, identified a meaningful association between menstrual cycle day and symptom score; this may need consideration when evaluating baseline and post-concussion symptom assessments in females. The correlation of salivary hormone measures to blood measures were investigated in chapter 5 in eight females to test feasibility for use in future studies. Progesterone was positively correlated between blood and saliva (rm=0.996, p<0.001). The findings of chapters 4 and 5 informed the protocols for chapters 6 to 8. In chapter 6, concussion biomarkers (salivary cortisol and miR-27a-5p/miR-30a-3p) were monitored in one player across three consecutive menstrual cycles in absence of injury during a football season. The biomarkers showed cyclical variation of miR ratio within a range of 0.7 to 1.1. The third menstrual cycle was shorter and showed significantly (p=0.031) lower miR ratio in the pre-menses compared to the menses phase. Morning cortisol stayed within a normal reference range (2-22 nmol/L) and showed a statistically significant mean difference between menses and pre-menses phases. Larger studies are needed to elucidate a clinically relevant threshold for miR ratio and must include reliable measures of hormone profile. Chapters 7 and 8 outlined the Female Ribonecleic Acid in Concussion (FeRNAC) study that sought to understand whether salivary miR-27a-5p/miR-30a-3p, symptoms and recovery time were associated with hormone profile in 36 females. Progestin only contraception (PROG) and the oral contraceptive pill (OCP) were significantly associated with a shorter time to RTL/W (HR = 2.5; 95% CI: 1.0 to 6.1; p=0.048 and HR = 2.7, 95% CI: 1.1 to 6.4; p=0.027 respectively). There was no statistically significant mean difference between groups for initial symptom score, F(2, 33)=1.755, p=0.189). Only 14 (39%) of saliva samples provided a full miR ratio, the mean miR ratio was 0.84± 0.06 (0.75 to 0.92) and there was no statistically significant difference between groups for miR-27/miR-30 (F(2, 11)=0.519, p=0.609). Chapter 9 discussed valuable areas of focus for future concussion research in females including recommendations for in-field research protocols. This final chapter provided narrative on reflective learning throughout the thesis.