Context: The cause of polycystic ovary syndrome (PCOS) is unknown, although genetic and environmental influences are clearly implicated. Some genetic studies have suggested the involvement of X-linked genes in PCOS, but the influence of X chromosome inactivation (XCI) on manifestation of this disorder has not previously been examined.

Objective: To test the null hypothesis that XCI has no influence on clinical presentation of PCOS.

Design: We examined patterns of XCI between sister pairs with the same genotype at a polymorphic locus on the X chromosome in families with PCOS.

Setting: Private practice

Participants: PCOS was defined as hyperandrogenaemia (HA) with chronic anovulation. Forty families were studied in which DNA was obtained from at least one parent, the proband, and one sister that could be accurately diagnosed as being affected or unaffected.

Main Outcome Measure(s): Relative expression of two X-linked alleles was determined and the ratio of one to the other represented the pattern of XCI.

Results: The statistical odds on a different clinical presentation between sisters was approximately 29 times higher in sister pairs with different patterns of XCI compared with sister pairs with the same pattern of XCI (OR = 28.9; 95% CI = 4.0 to 206; P = 0.0008).

Conclusions: This study provides evidence to refute the null hypothesis and propose a closer inspection of X-linked genes in PCOS, one in which both genotype and epigenotype are considered. Environmental determinants of PCOS may alter clinical presentation via epigenetic modifications, which currently remain undetected in traditional genetic analyses.