Beyond adrenal fatigue: reframing the adrenal stress index through neutrophil-mediated glucocorticoid resistance

Background: The Adrenal Stress Index (ASI) is widely used in functional medicine but dismissed by mainstream endocrinology. Traditionally interpreted as a measure of adrenal secretory capacity, it has been criticized for lacking clinical validity. Yet salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) may offer more than redundant hormone monitoring: they may capture the organism's ability to maintain resilience against chronic inflammation. Hypothesis: We propose that the ASI should be reframed not as a test of adrenal "fatigue," but as a candidate biomarker of inflammatory adaptation. Cortisol, bound to corticosteroid-binding globulin (CBG), is released at inflamed sites through neutrophil elastase stored in azurophilic granules. Since these granules are formed only at the promyelocyte stage, their depletion under chronic demand leads to neutrophil exhaustion and impaired cortisol delivery. DHEAS, conversely, buffers cortisol's catabolic and immunosuppressive actions and declines with age or persistent stress. The balance between cortisol exposure and DHEAS dynamics, therefore, reflects the efficiency of the HPA-immune-metabolic network rather than adrenal output alone. Supporting evidence: Flattened diurnal slopes, attenuated cortisol awakening response, evening-predominant DHEAS, and paradoxical elevations of salivary sex steroids under low cortisol/DHEAS conditions illustrate how chronic inflammation reprograms endocrine networks. These profiles align with clinical phenotypes such as frailty, sarcopenia, and metabolic dysfunction. Implications: Reframing the ASI as a measure of resilience highlights its potential as a research framework for investigating endocrine-immune adaptation. Standardized ELISA-based protocols, using fixed multi-timepoint daily sampling schemes, supported by LC-MS/MS validation, and the development of composite indices (e.g., cortisol AUC vs. DHEAS trapezoid gradient) may enhance reproducibility and predictive value. If validated in prospective cohorts, the ASI may provide a useful experimental tool for studying systemic adaptation in aging, chronic inflammation, and stress-related disorders. Conclusion: The ASI may provide a framework for investigating interactions between stress and inflammation. By bridging conventional endocrinology with functional perspectives, it may offer a conceptual framework for investigating inflammaging and biological resilience.