Differential Methylation of CYP11B1 in Girls with High DHEAS Levels and correlation with 11-Oxyandrogen levels: a pilot study.

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Premature adrenarche in girls is defined biochemically by an increase in adrenal androgen (DHEAS) levels above the age-specific reference range before age 8 years. Recently, increased levels of 11-oxyandrogens have also been reported in girls with premature adrenarche. Epigenetic modifications, specifically CpG methylation, may affect gene expression and/or activity of steroidogenic enzymes during developmental changes in adrenal androgen secretion. To determine whether circulating 11-oxyandrogen levels in post-menarcheal girls are associated with methylation status of genes involved in 11-oxyandrogen steroidogenesis. Ninety-seven healthy girls followed since the age of 3 years were classified, according to DHEAS serum concentration at age 6-7 years, as normal DHEAS (<42μg/dL [75th percentile for population]) or high DHEAS (≥42μg/dL). At Tanner stage 2, methylation status of CpG sites located in CYP11B1 and HSD11B2 genes were analyzed in genomic DNA from peripheral blood leukocytes by Melting Curve Analysis Methylation assay. Eleven-oxyandrogen concentrations were assessed at four years post menarche. Significantly lower methylation levels were detected in the CYP11B1 gene in girls with high versus normal serum DHEAS levels, with no differences found in HSD11B2 gene. Additionally, CYP11B1 methylation status correlated inversely with 11β-hydroxy-androstenedione and 11-ketotestosterone levels. Furthermore, CYP11B1 methylation in the full cohort correlated inversely with insulin concentration at Tanner 1 and with BMI at Tanner stage 1 and 2. This pilot study proposes the hypothesis that a lower methylation of CYP11B1 may be a mechanism contributing to increased concentrations of 11-oxyandrogens in premature adrenarche and its associated metabolic risk.