Journal of endocrinological investigation · 2026
Novel biomarkers to guide glucocorticoid replacement in primary adrenal insufficiency: a proof-of-concept study using copeptin-derived ratios.
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Bima Chiara, Campioni Lorenzo, Berton Alessandro Maria, Sola Chiara, Bergoglio Beatrice, Di Carlo Maria Chiara, Ponzetto Federico, Settanni Fabio, Ceccato Filippo, Parasiliti-Caprino Mirko, Giordano Roberta
Аннотация
BACKGROUND: Optimising glucocorticoid (GC) replacement in primary adrenal insufficiency (PAI) remains challenging, as clinical and biochemical markers do not reliably mirror tissue cortisol exposure.
OBJECTIVE: To evaluate salivary cortisone exposure and copeptin-derived ratios as candidate biomarkers of GC replacement adequacy in PAI.
DESIGN: Cross-sectional case-control study with 12-month follow-up including nineteen adults with autoimmune or idiopathic PAI on stable hydrocortisone (HC; immediate- or dual-release) plus fludrocortisone, and forty-three healthy controls.
METHODS: Six daytime saliva samples were collected for cortisol and cortisone quantification by LC-MS/MS. The area-under-the-curve (AUC) of cortisone was computed, and patients were classified as GC excess (AUC above the 90th percentile of controls; Group A) or adequate replacement (10th-90th percentile; Group B). Plasma ACTH, copeptin, renin, electrolytes and osmolarity were measured fasting and 120 min post-dose.
RESULTS: At baseline, 31.6% of patients showed GC excess, increasing to 36.8% at follow-up. Compared with Group B, Group A exhibited higher HbA1c (46.5 vs. 34.0 mmol/mol, p < 0.05) and diastolic blood pressure (84.5 ± 8.7 vs. 77.0 ± 9.6 mmHg, p < 0.05) with lower pulse pressure. ACTH and ACTH/copeptin ratios were markedly reduced in Group A both fasting (median 38.1 vs. 132.4) and post-dose (12.9 vs. 41.6), while renin/copeptin ratios declined at T1. ACTH/copeptin correlated inversely with cortisone AUC (r = - 0.59, p < 0.01).
CONCLUSIONS: Salivary cortisone AUC, together with ACTH/copeptin and renin/copeptin ratios, identifies physiologically distinct GC exposure profiles linked to metabolic and haemodynamic alterations. These biomarkers may refine personalised GC replacement in PAI.
OBJECTIVE: To evaluate salivary cortisone exposure and copeptin-derived ratios as candidate biomarkers of GC replacement adequacy in PAI.
DESIGN: Cross-sectional case-control study with 12-month follow-up including nineteen adults with autoimmune or idiopathic PAI on stable hydrocortisone (HC; immediate- or dual-release) plus fludrocortisone, and forty-three healthy controls.
METHODS: Six daytime saliva samples were collected for cortisol and cortisone quantification by LC-MS/MS. The area-under-the-curve (AUC) of cortisone was computed, and patients were classified as GC excess (AUC above the 90th percentile of controls; Group A) or adequate replacement (10th-90th percentile; Group B). Plasma ACTH, copeptin, renin, electrolytes and osmolarity were measured fasting and 120 min post-dose.
RESULTS: At baseline, 31.6% of patients showed GC excess, increasing to 36.8% at follow-up. Compared with Group B, Group A exhibited higher HbA1c (46.5 vs. 34.0 mmol/mol, p < 0.05) and diastolic blood pressure (84.5 ± 8.7 vs. 77.0 ± 9.6 mmHg, p < 0.05) with lower pulse pressure. ACTH and ACTH/copeptin ratios were markedly reduced in Group A both fasting (median 38.1 vs. 132.4) and post-dose (12.9 vs. 41.6), while renin/copeptin ratios declined at T1. ACTH/copeptin correlated inversely with cortisone AUC (r = - 0.59, p < 0.01).
CONCLUSIONS: Salivary cortisone AUC, together with ACTH/copeptin and renin/copeptin ratios, identifies physiologically distinct GC exposure profiles linked to metabolic and haemodynamic alterations. These biomarkers may refine personalised GC replacement in PAI.