Novel biomarkers to guide glucocorticoid replacement in primary adrenal insufficiency: a proof-of-concept study using copeptin-derived ratios

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.