Hydrocortisone – systemic use

Additional information

Pharmacokinetics and dosing

Hydrocortisone is the synthetic form of endogenous cortisol. The pharmacokinetics of cortisol is dose-dependent as normally 90% is protein bound but the protein-binding diminishes with  higher concentrations [4]. The pharmacokinetics of cortisol was examined in children and adolescents with congenital adrenal hyperplasia (CAH) administrated hydrocortisone IV (15 mg/m2 body surface area) (14 boys, 26 girls). At inclusion, all patients were on replacement therapy with hydrocortisone. After adjustment for BMI, boys had 27% higher mean total clearance than girls, whereas free cortisol clearance was similar in boys and girls. Boys had higher mean volume of distribution of both total and free cortisol, after adjustment for BMI. Half-life of total cortisol was similar in boys and girls, but half-life of free cortisol was 25% shorter in girls [5].A retrospective study of pubertal children with CAH showed that boys received higher average hydrocortisone doses than girls (mean 16.4 vs. 13.7 mg/m2/day). The sex difference in dosage was significant at the puberty scale Tanner stages 3-5 [6].

Effects

Growth and pubertal development in children with CAH on treatment with hydrocortisone acetate, cortisone acetate, or prednisone has been investigated (8 boys, 10 girls). Growth was evaluated according to Tanner’s standards. Boys had earlier onset of puberty, but not girls, and the authors speculate that this might be due to induction through hypothalamic stimulation by androgens [7].The effect of oral hydrocortisone replacement therapy on serum gonadotropin levels were studied in girls with CAH (9 girls, age 5-29 days) and compared with a control group (16 girls aged 27-90 days old, 15 boys aged 20-90 days old). Before treatment, girls with CAH had similar serum LH levels as healthy girls while FSH levels were lower than in healthy girls and similar as in healthy boys. After treatment, girls with CAH had higher serum LH levels than healthy girls and similar as healthy boys, FSH levels were similar to healthy girls [8].A randomized double-blind cross-over study (29 men, 18 women) investigated whether hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients. Adult patients were randomized to receive high-dose hydrocortisone (0.4-0.6 mg/kg) for 10 weeks followed by low-dose hydrocortisone (0.2-0.3 mg/kg) for 10 another weeks, or vice versa. The higher dose hydrocortisone resulted in an on average 10% increase of total bilirubin. No differences between men and women were seen [9].The effect of hydrocortisone in patients with septic shock was compared to methylprednisolone (125 men, 75 women). Patients received either hydrocortisone i.v. 50 mg every 6 h or methylprednisolone 20 mg every 12 h, for 7 days. The two treatment groups were similar in terms of survival rates and time to reverse. There were no differences between men or women [10].The effect of neonatal hydrocortisone treatment on behavior and motor development in children at school age was retrospectively compared to neonatal dexamethasone treatment, antenatal betamethasone-treated preterm born infants and preterm infants with no glucocorticoid treatment (in total 108 boys, 84 girls). Girls treated with dexamethasone as infants had poorer scores than those treated with hydrocortisone. Boys did not differ between treatment groups. Boys and girls treated with hydrocortisone as infants had similar results as boys and girls in the reference group and betamethasone group [11].

Adverse effects

A large meta-analysis of corticosteroid-induced osteoporosis in adults showed that oral corticosteroid treatment with doses above 5 mg/day (of prednisolone or equivalent) reduced bone mineral density and increased the risk of fracture during treatment, irrespective of age, sex, or underlying disease (66 studies with 2891 patients with BMD measures, 71.5% women and 23 studies with 558 with fractures in corticosteroid users, and 244 235 corticosteroid users with fractures in the General Practice Research Database) [1]. However, a study not included in the meta-analysis, retrospectively analyzed the population attributable risk of fracture in a cohort using oral corticosteroids (8192 men, 12034 women). Compared to the general population, corticosteroids users had a higher risk of fracture (RR 1.90), and women had a higher risk than men (RR 2.13) [2]. Another meta-analysis of glucocorticoid therapy in children (in total 287 patients with BMD measure, and 37 819 with fractures) showed corticosteroid use to be associated with reduced spine bone mineral density and no sex difference in the risk for fracture were seen [3].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).