OBJECTIVES: The authors independently extracted and analysed the data from different interventions. They undertook the comparisons separately and used GRADE to assess the quality of the evidence.
MAIN RESULTS: Searches identified 1729 records with 43 records subject to further examination. After screening, we included five RCTs (six references) with a total of 101 participants and identified a further six ongoing RCTs. The number of participants in each trial varied from six to 44, with participants' ages ranging from 3.6 months to 21 years. Four trials were of cross-over design and one was of parallel design.
Duration of treatment ranged from two weeks to six months per treatment arm with an overall follow-up between six and 12 months for all trials. Overall, we judged the quality of the trials to be at moderate to high risk of bias; with lack of methodological detail leading to unclear or high risk of bias judgements across many of the domains. All trials employed an oral
glucocorticoid replacement
therapy, but with different daily schedules and dose levels. Three trials compared different dose schedules of
hydrocortisone (HC), one three-arm trial compared HC to
prednisolone (PD) and
dexamethasone (DXA) and one trial compared HC with
fludrocortisone to PD with
fludrocortisone. Due to the heterogeneity of the trials and the limited amount of evidence, we were unable to perform any meta-analyses. No trials reported on quality of life, prevention of adrenal crisis, presence of
osteopenia, presence of testicular or ovarian adrenal rest tumours,
subfertility or final adult height. Five trials (101 participants) reported
androgen normalisation but using different measurements (very low-quality evidence for all measurements). Five trials reported
17 hydroxyprogesterone (17 OHP) levels, four trials reported
androstenedione, three trials reported
testosterone and one trial reported
dehydroepiandrosterone sulphate (DHEAS). After four weeks, results from one trial (15 participants) showed a high morning dose of HC or a high evening dose made little or no difference in 17 OHP,
testosterone,
androstenedione and DHEAS. One trial (27 participants) found that HC and DXA treatment suppressed 17 OHP and
androstenedione more than PD treatment after six weeks and a further trial (eight participants) reported no difference in 17 OHP between the five different dosing schedules of HC at between four and six weeks. One trial (44 participants) comparing HC and PD found no differences in the values of 17 OHP,
androstenedione and
testosterone at one year. One trial (26 participants) of HC versus HC plus
fludrocortisone found that at six months 17 OHP and
androstenedione levels were more suppressed on HC alone, but there were no differences noted in
testosterone levels. While no trials reported on absolute final adult height, we reported some
surrogate markers. Three trials reported on growth and bone maturation and two trials reported on height velocity. One trial found height velocity was reduced at six months in 26 participants given once daily HC 25 mg/m²/day compared to once daily HC 15 mg/m²/day (both groups also received
fludrocortisone 0.1 mg/day), but as the quality of the evidence was very low we are unsure whether the variation in HC dose caused the difference. There were no differences noted in
growth hormone or IGF1 levels. The results from another trial (44 participants) indicate no difference in growth velocity between HC and PD at one year (very low-quality evidence), but this trial did report that once daily PD treatment may lead to better control of bone maturation compared to HC in prepubertal children and that the absolute change in bone age/chronological age ratio was higher in the HC group compared to the PD group.
AUTHORS' CONCLUSIONS: There are currently limited trials comparing the efficacy and safety of different
glucocorticoid replacement regimens for treating
21-hydroxylase deficiency CAH in children and adults and we were unable to draw any firm conclusions based on the evidence that was presented in the included trials. No trials included long-term outcomes such as quality of life, prevention of adrenal crisis, presence of
osteopenia, presence of testicular or ovarian adrenal rest tumours,
subfertility and final adult height. There were no trials examining a modified-release formulation of HC or use of 24-hour circadian continuous
subcutaneous infusion of
hydrocortisone. As a consequence, uncertainty remains about the most effective form of
glucocorticoid replacement
therapy in CAH for children and adults. Future trials should include both children and adults with CAH. A longer duration of follow-up is required to monitor biochemical and clinical outcomes.