The role of oral contraceptive use in associations of concussion history with kynurenine pathway metabolites, inflammation, and psychological symptoms in female athletes

Concussion history is linked to increased risk of psychological symptoms, potentially through inflammation-driven activation of the kynurenine pathway (KP). Use of oral contraceptives (OC) is also associated with increased inflammation, reduced protective kynurenic acid (KynA), and, in some cases, increased psychological symptoms. Despite this evidence and the fact that around half of all female collegiate athletes use OCs, existing research in this area does not account for OC use among female athletes. In this study, we tested the hypothesis that OC use moderates the association of number of prior concussions with serum inflammatory markers and KP metabolites and self-reported psychological symptoms. Collegiate female athletes (N = 69; 30 using OC) participating in a larger cross-sectional study completed semi-structured interviews to retrospectively determine the number of prior concussions (last injury at least 6 months before study enrollment). Linear models assessed associations between the number of prior concussions, OC use, and their interaction with outcomes, controlling for contact-sport exposure. Split analyses tested these associations in athletes using OC versus those not using hormonal contraception (NoHC). Additional exploratory linear models assessed associations between the number of prior concussions, hormonal activity levels of OC, and their interaction on outcomes, controlling for contact-sport exposure. Higher number of prior concussions was associated with elevated quinolinic acid (QuinA), interleukin (IL)-1 receptor antagonist, and psychological symptoms. Although there was no significant interaction, split analyses showed these relationships held only in the NoHC group. Moreover, compared to the NoHC group, OC users exhibited higher C-reactive protein and IL-6 and lower KynA, KynA/QuinA, and KynA/3-hydroxykynurenine. OC formulation moderated biomarker associations in this cohort, with higher progestational and androgenic activity linked to a more proinflammatory profile and greater KP activation with more prior concussions. The results highlight OC use as a potential moderator of the cumulative psychological/immunological effects of repeat concussion in female athletes that should be considered when personalizing treatment for individuals with multiple injuries.