Hair cortisol as a marker of glucocorticoid replacement adequacy in adrenal insufficiency

Background: Achieving physiologic glucocorticoid replacement in adrenal insufficiency (AI) remains challenging, as both under- and over-replacement contribute to morbidity. Hair cortisol concentration (HCC) reflects cumulative cortisol exposure and may provide clinically relevant information beyond single-time-point assessments. Methods: In this cross-sectional study, 64 adults with hydrocortisone-treated AI and 64 matched healthy controls were evaluated. HCC was measured from the proximal 3-cm hair segment. Clinical, anthropometric, metabolic, and dosing parameters were analyzed. Patients were categorized as undertreated (VAS-fatigue or VAS-pain ≥7) or overtreated (hypertension, hyperglycemia, or ≥5% weight gain). Correlation, ROC, and multivariable regression analyses were performed. Results: HCC was higher in AI patients than controls (4.3 vs. 1.75 ng/g, p < 0.01). In AI, HCC was higher in primary than in secondary disease (6.5 vs. 3.8 ng/g; p = 0.037); this difference remained significant after excluding patients with congenital adrenal hyperplasia (13.8 vs. 3.8 ng/g; p < 0.01). HCC was positively correlated with BMI, waist circumference, blood pressure, and hydrocortisone dose, and inversely correlated with fatigue, pain, and therapy duration (all p < 0.05). In multivariable analysis, AI subtype remained independently associated with HCC. When the AI subtype was excluded from the model, hydrocortisone dose emerged as an independent predictor. HCC demonstrated excellent discrimination for severe fatigue (AUC 0.906) and pain (AUC 0.898), and good performance for systolic hypertension (AUC 0.837). Undertreated patients had markedly lower HCC than overtreated patients (2.1 vs. 14.1 ng/g, p < 0.001). Conclusions: HCC reflects long-term glucocorticoid exposure in AI and differentiates patterns consistent with both underreplacement and overtreatment. These findings support HCC as a potential adjunctive tool for evaluating replacement adequacy. Prospective studies are needed to determine its role in dose optimization.