Novel insights into the puberty switch mechanisms of the sex bias in human asthma

Abstract

Abstract The gender bias in human asthma prevalence changes with puberty, with males having a higher asthma incidence before puberty and females having higher rates after. The mechanisms involved in this switch are unknown. Our previous research showed that multiple hormonal systems are dysregulated in allergic disease. Because sex hormones interact with all endocrine system axes, we hypothesized that non-sex hormones and their downstream functions in allergic disease are driven by sex related changes in puberty. Measuring non-sex hormone protein levels from human serum samples by multiplex ELISAs, we found a striking sexual dimorphism in endocrine regulation. Pre-puberty asthmatic males had higher T3, T4, and GH levels compared to healthy controls, and pre-puberty asthmatic females had lower C-peptide and insulin levels. Interestingly, we saw the opposite pattern post-puberty. In a kinetic murine ovalbumin asthma model, adult male mice had higher C-peptide and insulin baseline levels, which were maintained during inflammation. Males also had higher GIP levels in the acute phase and higher PP, PYY, and resistin levels in the model’s late phase. Since hormones regulate tissue homeostasis, we examined the puberty switch in key epithelial remodeling markers in the inflamed mouse lung. Thbs2, Nes, Postn, Tnc, and Wnt5a expression was different relative to baseline in both sexes pre-puberty, but only females had altered expression of these markers post-puberty. Interestingly, though the Th2 immune response was higher in females post-puberty, there was no sexual dimorphism pre-puberty. These results implicate that sex hormones exert systemic level regulation determining the age and gender dependent progression of asthma pathogenesis.