{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:45:31Z","timestamp":1783014331326,"version":"3.54.6"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2019s ability to maintain resilience against chronic inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Hypothesis<\/jats:title>\n                    <jats:p>We propose that the ASI should be reframed not as a test of adrenal \u201cfatigue,\u201d but as a candidate biomarker of inflammatory adaptation. Cortisol, bound to corticosteroid\u2013binding 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\u2019s 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\u2013immune\u2013metabolic network rather than adrenal output alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supporting evidence<\/jats:title>\n                    <jats:p>Flattened diurnal slopes, attenuated cortisol awakening response, evening\u2013predominant 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications<\/jats:title>\n                    <jats:p>Reframing the ASI as a measure of resilience highlights its potential as a research framework for investigating endocrine\u2013immune adaptation. Standardized ELISA\u2013based protocols, using fixed multi-timepoint daily sampling schemes, supported by LC\u2013MS\/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\u2013related disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1785454","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T05:23:38Z","timestamp":1773897818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond adrenal fatigue: reframing the adrenal stress index through neutrophil-mediated glucocorticoid resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Giuseppe","family":"Cardillo","sequence":"first","affiliation":[{"name":"MEDYLAB S.r.l.","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2009.06.011","article-title":"Assessing salivary cortisol in large-scale, epidemiological research","volume":"34","author":"Adam","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1037\/a0017910","article-title":"Interindividual differences and intraindividual variability in the cortisol awakening response: an examination of age and gender","volume":"24","author":"Almeida","year":"2009","journal-title":"Psychol Aging"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1177\/000456328302000601","article-title":"Salivary cortisol: a better measure of adrenal cortical function than serum cortisol","volume":"20","author":"Vining","year":"1983","journal-title":"Ann Clin Biochem"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4530(94)90013-2","article-title":"Salivary cortisol in psychoneuroendocrine research: recent developments and applications","volume":"19","author":"Kirschbaum","year":"1994","journal-title":"Psychoneuroendocrinology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2008.10.026","article-title":"Salivary cortisol as a biomarker in stress research","volume":"34","author":"Hellhammer","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.psyneuen.2008.10.004","article-title":"Why do we respond so differently? 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