Androgen receptor-mediated hypersensitivity to androgens in women with nonhyperandrogenic hirsutism: Skewing of X-chromosome inactivation

Idiopathic hirsutism may result from an increase in the androgen receptor ( AR)-mediated sensitivity of the hair follicle. The AR gene is located on th e X-chromosome and contains a highly polymorphic trinucleotide repeat (CAGn ) in its first exon, whose length and methylation pattern affect both AR ex pression and function. We analyzed these CAG repeats in the genomic DNA fro m 16 nonhyperandrogenic hirsute patients (Ferriman score: 16 +/- 4.7, mean +/- SD) and 10 normal controls (Ferriman score: 3 +/- 1.4), who were simila r in their hormonal profiles. We found no difference in the number of CAG r epeats between hirsute patients and controls, and no correlation between nu mber of repeats and the Ferriman score or hormonal values. However, alter D NA digestion with methylation-sensitive HpaII and measurement of the optica l density, we found a marked decrease in the hirsute group (P < 0.0001), wh ich was greater than in the control group (P = 0.0003). In addition, in the hirsute patients, the shorter of the two alleles was preferentially less m ethylated (P = 0.007), suggesting skewing of X-chromosome inactivation in t he patients but not in the controls. When the mean optical density of both alleles was correlated with the Ferriman score, we observed a significant n egative correlation (P = 0.02, r = -0.45), which became stronger when the s horter alleles were analyzed separately (P = 0.01; r = -0.48). We conclude that nonhyperandrogenic hirsutism is associated with skewing of X-chromosom e inactivation in peripheral blood lymphocytes. This leads to the longer of the two AR alleles being preferentially methylated, allowing for the short er land presumably, more functional) allele to be expressed on the active X -chromosome. Further studies need to be performed to investigate whether th is phenomenon is present in androgen-sensitive tissues in these patients.