Progesterone and Estradiol Levels Associated with Concussion and Clinical Outcomes and Recovery in Female Athletes and Cadets

Introduction: Female athletes are underrepresented in concussion research, and few studies have investigated associations of ovarian hormones with concussion outcomes. This study explored associations of concussion with levels and variability of progesterone, estradiol, and their ratio (P/E) and examined relationships of hormone levels with clinical measures and recovery after concussion in CARE Consortium female athletes and cadets.Methods: Female participants enrolled (n = 749) at pre-injury baseline. Participants with concussion (mean age 19.34 years; n = 130, 90 athletes, 40 non-athlete cadets) completed one or more visits at non-standardized times of day: immediately post-injury, 24-hours post-injury, upon initiating the return-to-play protocol (Init RTP), and seven days following unrestricted return-to-play (PRTP). Controls (mean age 19.85 years; n = 67, 61 athletes, 6 non-athlete cadets) completed similar visits. Linear mixed models and general linear models tested associations of hormone levels and/or variation with concussion status, symptoms, and recovery, controlling for self-reported birth control use at pre-injury baseline.Results: Female participants with concussion had higher progesterone levels relative to controls on average across all visits (mean difference (ln ng/mL) (standard error) MD = 0.26(0.08), t(193) = 3.03, p = 0.003). Those with concussion had elevated estradiol at 24 hours (MD = 0.27(0.09), t(506) = 3.04, p = 0.02), Init RTP (MD = 0.38(0.09), t(508) = 4.29, p < 0.001), and PRTP (MD = 0.30(0.09), t(515) = 3.25, p = 0.01) relative to pre-injury baseline, and compared to controls at Init RTP (MD = 0.35(0.12), t(429) = 2.78, p = 0.006). Concussed participants had a lower range of estradiol over 7-28 days than controls (B(SE) = -0.24(0.09), F(1,145) = 6.43, p = 0.01). Acutely after concussion, estradiol was positively associated with Brief Symptom Inventory Global Severity Index scores (B(SE) = 0.29(0.12), F(1,102) = 5.60, p = 0.02). No significant relationships were found between hormones and recovery.Conclusions: These results, which warrant further research, suggest ovarian hormones may be associated with concussion and psychological symptom severity post-concussion.