Dexamethasone prophylaxis in sex-based respiratory complications under acute hypobaric hypoxia

Dexamethasone and acetazolamide, among others, can be taken prophylactically to prevent hypobaric hypoxia-associated high-altitude disorders. While dexamethasone-mediated protection against high-altitude disorders has been clinically evaluated, detailed sex-based mechanistic insights have yet to be explored. This study aimed to investigate sex-based drug prophylaxis for respiratory problems under hypobaric hypoxia at high-altitude. As part of our India-Leh-Dexamethasone-expedition-2020 and -2022 (INDEX2020 and 2022) programmes, we examined the phenotype of control (n = 14) and dexamethasone (n = 13) groups, which were airlifted from Delhi (~225 meters elevation) to Leh, Ladakh (~3,500 meters above sea-level), India, for three days. Dexamethasone 4 mg twice daily significantly attenuated the drop in SpO₂ and increased blood pressure, heart rate, pulmonary pressure and circulating biomarkers resulting from high-altitude exposure compared to controls (P<0.05). Of interest, the positive effect of dexamethasone was substantially more significant in women than in men (P<0.05). Thus, for the first time, this study shows a sex-based regulation by dexamethasone of physiologic parameters resulting from the hypobaric hypoxic environment, which impacts the development of high-altitude pulmonary hypertension and acute mountain sickness. Future studies of cellular contributions toward sex-specific regulation may provide further insights and preventive measures in managing sex-specific, high-altitude-related disorders.