Chronopharmacology of hydrocortisone and 9?-fluorhydrocortisone in the treatment for congenital adrenal hyperplasia

Abstract

The conventional treatment of CAH with hydrocortisone (16-19 mg/m2 per day) and 9 alpha-F-cortisol (just enough to normalise renin concentrations, started at 07:00 h) was ineffective in suppressing the early morning rise of 17-OH-progesterone and in turn androgens in about 20% of our patients. The present work explored the effect of a modified dosage regimen of the drug in five patients. The schedule was: 03:00 h F 33% + 9 alpha-F-F 33%; 07:00 h F 30%; 12:00 h F 22% + 9 alpha-F-F 33%; 17:30 h F 15% + 9 alpha-F-F 33%. Monitored levels of circulating 17-OH-progesterone, testosterone, and individual urinary 17-ketosteroids showed significant improvement, which was not achieved by giving higher or later evening doses. Menarche was induced in two girls (bone age 15 years). The modified dosage schedule offers on the one hand the possibility of better management of CAH, and on the other, cuts down the risk of enhanced Cushing-like effects, which in animal models have been related frequently to dosage schedules not corresponding to the circadian rhythm. The difficulty of administering the drugs at 03:00 h should be overcome by the development of a late-releasing preparation.

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life

“…In our cohort, daily hydrocortisone doses in the lower range of the recommended 10-15 mg/m 2 daily, and medication timetables resulting in a longer cortisol night gap, may have contributed to a predisposition to hypoglycemia. Thus, altered dosage recommendations for young CAH children or new drugs with a delayed hydrocortisone release providing higher cortisol levels in the early morning hours (44,45) could be promising approaches in the future. Probably not all classic CAH patients are equally at risk for hypoglycemia.…”

Serum Cortisol and 17-Hydroxyprogesterone Interrelation in Classic 21-Hydroxylase Deficiency: Is Current Replacement Therapy Satisfactory?

“…Therefore, it may be more appropriate, although not practical, to administer a dose of hydrocortisone just before the time of the rapid rise in 17OHP concentrations early in the morning (25).…”

Review: Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy

“…An alternative regime is waking to take immediate-release hydrocortisone dose at 03:00, and such an approach resulted in a significant improvement in 17OHP, testosterone and individual urinary 17-ketosteroids in five patients with congenital adrenal hyperplasia. This was not achieved by giving doses which were either higher or taken later on in the evening [Moeller, 1985]. Although effective this strategy is not practical as this would mean interrupting patients' sleep and only extremely cooperative patients would benefit.…”