Decreased androgen receptor gene methylation in premature pubarche: a novel pathogenetic mechanism?

Context: Several studies found links between DNA methylation and gene expression. In patients with idiopathic hirsutism, a preferential methylation of the of shorter androgen receptor (AR) alleles was hypothesized to be responsible for the abnormal hair growth. Objective: The objective of this study was to assess whether abnormalities in the AR function in both peripheral blood leukocytes (PBLs) and androgen target tissues are present in children with premature pubarche (PP). Design: Human DNA was extracted from PBLs and pubic hair and CAG repeats length and methylation status of the AR gene were analyzed. Setting: The study was performed at a Pediatric Endocrinology referral clinic. Patients: Twenty-five girls with PP, 23 prepubertal children, and 10 girls with Tanner stage II pubertal development were studied. Main Outcome Measure: The main outcome measures were CAG repeat length and AR methylation pattern in PBLs and pubic hair. Results: In PBLs from PP patients, AR gene methylation was significantly lower (P < 0.01) than that of prepubertal children and similar to that of girls with Tanner II stage pubertal development. A negative correlation between AR gene methylation in PBLs and the age of normal children was detected. Patients with PP exhibited a hair follicle AR methylation pattern similar to that of Tanner stage II girls. The mean number of CAG repeats was lower in PP patients than in prepubertal and Tanner stage II girls, although it was within the normal range for the general population in both groups. Conclusions: The increased AR gene activity observed in PP patients, as indicated by the reduced AR gene methylation pattern, together with the presence of shorter CAG repeats, might lead to hypersensitivity of the hair follicles to steroid hormones and therefore to the premature development of pubic hair.