The role of the CAG repeat polymorphism in the androgen receptor gene and of skewed X-chromosome inactivation, in the pathogenesis of hirsutism.

The human androgen receptor (AR) gene contains a variable number of CAG repeats within exon 1. Shorter AR alleles, by increasing transactivation, may result in augmented AR-mediated sensitivity of the hair follicle. We have evaluated whether the number of CAG repeats, or if skewed inactivation of X-chromosome, favoring the presence of shorter AR alleles, influence hirsutism in women with and without hyperandrogenemia. Twenty-eight women with idiopathic hirsutism (normal serum androgens), 34 women with hyperandrogenic hirsutism (increased serum androgens), and 15 healthy control women were analyzed by evaluating the number of CAG repeats in genomic DNA, as well as the methylation pattern (after DNA digestion with HpaII), which allows identification of which allele is inactive. Despite marked differences among the groups in serum androgens, which were markedly increased in women with hyperandrogenic hirsutism as compared with women with idiopathic hirsutism and to controls, there were no significant differences among the groups in the number of CAG repeats. Moreover, skewed X-chromosome inactivation was found in 10 subjects (3 with idiopathic hirsutism, 5 with hyperandrogenic hirsutism, and 2 controls; P = 0.746) of the 67 women (14.9%) who were heterozygous for the AR gene. In several of these subjects, it was the shorter allele that was preferentially inactivated. In conclusion, neither the CAG repeat polymorphism in the AR gene, nor skewed X-chromosome inactivation, seem to play a significant role in the pathogenesis of hirsutism.