Background: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice-daily, but there is debate about the optimal timing of highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening).

Objective: The primary aim was to compare two standard HC timing strategies, either highest dosage in the morning or highest dosage in the evening, with respect to hormonal status throughout the day. The secondary objective was to evaluate these treatment regimens with respect to nocturnal blood pressure, and sleep and activity scores.

Patients and interventions: A six-week cross-over study was performed. Thirty-nine patients (4-19 years) with 21OHD were treated for three weeks with highest hydrocortisone dose in the morning, followed by three weeks with highest dose in the evening (n=21), or vice-versa (n=18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5.00 am; 7.00 am; 3.00 pm; and 11.00 pm during the last two days of each treatment period. Overnight blood pressure was measured in the last week of each treatment period and sleeping and activity scores were reported for each day during the entire six-week period.

Results: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5.00 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The two treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal blood pressure, and activity and sleep scores.

Conclusion: No clear benefit for either treatment schedule was established. Given the variation in individual responses we recommend to individually optimize dose distribution and monitoring disease control at multiple timepoints.