Metabolomic signatures of the steroid biosynthesis driving sex differences in clinical asthma subtypes

Background: Asthma is a heterogeneous disease with well-documented sex differences in prevalence. However, the sex-specific and pubertal effects of inhaled corticosteroids on endogenous steroid metabolites and their relationship with asthma-related clinical outcomes remain poorly understood. Methods: Targeted whole-blood plasma profiling of the steroid biosynthesis pathway was generated by Precion Inc. (NC, USA). Sixteen metabolites from the steroid biosynthesis pathway were quantified at baseline and end-of-trial in children with asthma from the Childhood Asthma Management Program (CAMP; n=1,041), aged 5-12 years. Linear mixed models and generalized linear models were used to evaluate sex-specific longitudinal and endpoint responses of steroid metabolites and clinical outcomes with inhaled corticosteroid (ICS) use, adjusting for age, sex, race, height, and body mass index. Results: ICS use in males was associated with significantly lower cortisol and cortisone levels at Year 4 (end of trial). In females, cortisol and cortisone showed more stable trajectories with ICS use, which resulted in a non-significant reduction at year 4. Males receiving ICS showed suggestive positive longitudinal associations for 17α-hydroxyprogesterone, estrone, and testosterone, while females showed a suggestive positive trajectory for androstenedione. ICS exposure modified the associations between metabolites and clinical outcomes (FEV1, FVC, eosinophils, and airway hyperresponsiveness) in a pathway- and sex-specific manner. Overall, ICS attenuated longitudinal associations between endogenous steroids and clinical outcomes, particularly in females, while selected relationships from the androgen-lung function associations were preserved at the end of the trial. Conclusion: We identify sex-specific differences in ICS-associated metabolite profiles and clinical outcomes, supporting the need for further investigation into sex-informed approaches to corticosteroid use in pediatric asthma. Trial registration: Clinicaltrials.gov: NCT00000575; registered 1999-10-27.