Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Abstract

INTRODUCTION:21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed.OBJECTIVE:The present study aimed to evaluate the association between polymorphic variants involved in glucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients.METHODS:We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels.RESULTS:The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean±SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9±0.8 and 19.5±3.2 mg/m2/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose.CONCLUSION:Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed, the CYP3A7*1C allele accounted for 20% of the variability in the cortisone acetate dose. The analysis of genes involved in glucocorticoid metabolism may be useful in the optimization of treatment of 21-hydroxylase deficiency.

Obesity and Familial Predisposition Are Significant Determining Factors of an Adverse Metabolic Profile in Young Patients with Congenital Adrenal Hyperplasia

“…Current GC therapy aims to provide adequate GC replacement and, when necessary, mineralocorticoid replacement; this is necessary both to prevent adrenal crisis and to suppress increased androgen secretion, thus enabling the patient to attain a normal final height without any signs of hypercortisolism. During the growth period, GCs with a short half-life are preferred to avoid growth suppression [1,5,6]. In contrast, during adulthood, a long-acting GC is preferred for possible better compliance with long-term therapy [7].…”

Pharmacogenetics of drug metabolizing enzymes in Brazilian populations

“…The PGx of the CYP3A7*1C variant was evaluated in Brazilian children with congenital adrenal hyperplasia due to 21-hydroxilase deficiency submitted to glucocorticoid replacement therapy [74]. The authors reported lower cortisone acetate requirements for CYP3A7*1C allele carriers (Table 2).…”

Influence of the A3669G Glucocorticoid Receptor Gene Polymorphism on the Metabolic Profile of Pediatric Patients with Congenital Adrenal Hyperplasia

“…The introduction of glucocorticoid (GC) replacement leads to significant improvement in the prognosis of classical forms. During growth periods, preference is given to the use of short half-life glucocorticoids that avoid growth suppression [ 1 , 5 , 6 ], and after the achievement of final height, the use of long-acting GC is suggested to allow better compliance for long-term therapy [ 7 ].…”