X‐inactivation (lyonization), the compensatory mechanism by which balanced gene dosage is achieved between (XY) males and (XX) females is another important concept in investigating sex differences in disease. In general, there is random inactivation of one X chromosome that varies in each cell. However, one intriguing finding that is worthy of further study is the extent to which some genes escape X‐inactivation. 49 Approximately 15% of genes on the X chromosome are not inactivated in females. Among males no differences in expression levels between escape genes and inactivated genes have been reported; however, the degree to which escape genes are inactivated in females varies between cells, tissues, genes and individuals. 50 Moreover, it is theorized that genes outside of the pseudo‐autosomal region must be upregulated on the male X in order to maintain function. 48 X‐inactivation escape genes have been associated with cognitive impairment, 51 and a recent report shows an association between genes that escape X inactivation and sex differences in the prevalence of comorbid musculoskeletal pain and posttraumatic stress symptoms after motor vehicle accidents. 52 There has been
