Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Chronic asthma affects 5%~10% of adults worldwide. Glucocorticoids (GCs) serve as first-line treatment, yet glucocorticoid resistance (GCR) in severe asthma complicates clinical management. Thyroid hormone (TH) and the hypothalamic-pituitary-adrenal (HPA) axis interact to modulate GC sensitivity via understudied endocrine pathways. Objectives: This scoping review summarizes TH–HPA regulatory mechanisms underlying GCR, summarizes available evidence and endocrine-targeted therapeutic prospects. Methods: Literature was searched from PubMed (n=487), Embase (n=412) and Web of Science (n=348) from 1 January 2015 to 15 January 2026 in accordance with the PRISMA 2020 framework. The search retrieved 1247 records. After removing 312 duplicates and 47 records marked as ineligible by automation tools, 888 records underwent title/abstract screening, yielding 87 potentially eligible studies. Full-text assessment excluded 59 studies for specific reasons: 32 studies involved non-asthma populations; 18 studies lacked sufficient mechanistic data on TH-HPA-GR interactions; 9 studies were non-English publications without available translations. Ultimately, 28 studies (15 in-vitro/cell studies, 9 animal models, 4 cross-sectional clinical studies) were included in this qualitative synthesis. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies (scores ranging 6-8 stars) and SYRCLE's risk of bias tool for animal studies (2 studies rated high risk, 7 moderate risk). The search terms included “chronic asthma”, “glucocorticoid resistance”, “thyroid hormone”, “hypothalamic-pituitary-adrenal axis” and “endocrine modulation”. Results: TH alters GC sensitivity through glucocorticoid receptor phosphorylation, immune homeostasis and airway smooth muscle regulation. HPA insufficiency lowers endogenous cortisol and GR expression to drive GCR. TH-HPA crosstalk aggravates persistent inflammation, but supportive evidence mostly comes from preclinical research with scarce high-quality clinical data. Conclusion: Modulating TH-HPA interplay is promising for GCR reversal. Further rigorous clinical trials are required to verify clinical efficacy before routine therapeutic translation.