Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency

OBJECTIVES. Studies of adults have shown that thrice-daily hydrocortisone dosing results in more physiologic cortisol profiles than twice-daily dosing. There are no data on thrice-daily dosing and only limited data on twice-daily dosing in children despite the possible adverse effects of glucocorticoid underreplacement or over-replacement. METHODS. Using 24-hour cortisol and glucose profiles, along with computerized cognitive testing, our aim was to assess prescribed hydrocortisone regimens in children and adolescents with hypopituitarism. RESULTS. Twenty patients with adrenocorticotrophic hormone deficiency participated. The hydrocortisone dosing regimen was thrice daily in 9 patients and twice daily in 11 patients (mean total daily dose: 8.3 +/- 2.6 and 7.6 +/- 2.1 mg/m(2) per day, respectively). Those on twice-daily dosing had more waking hours (between 8: 00 AM and 8: 00 PM) below the reference range than those on thrice- daily dosing (5.5 vs 2.1) and more daytime prolonged hypocortisolemia, defined as plasma cortisol level of < 50 nmol/L for >= 4 hours (64% vs 0%). Morning doses > 4 mg/m(2) caused larger postdose peaks than < 4 mg/m(2) (151 vs 47 nmol/L, above the 97.5th percentile). However, there was no difference in the length of time taken to reach nadir below the 2.5th percentile (5.2 vs 4.8 hours). This was true for evening doses of > 2.5 mg/m(2) and < 2.5 mg/m(2). No hypoglycemia or hyperglycemia was detected in association with low or high cortisol levels. On predose and postdose cognitive testing (34 paired tests), no significant change in reaction speed was detected (453.3 vs 438.8 milliseconds) or in subgroup analysis of those who had symptoms of lethargy, predose cortisol levels of < 50 nmol/L, or prolonged hypocortisolemia. CONCLUSIONS. Thrice- daily dosing resulted in less frequent and prolonged hypocortisolemia than twice-daily regimens, but we were unable to relate either regimen to acute clinical end points of glycemia, lethargy, or cognitive function.