Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical

• We imaged responses to sexual images in 46,XY men, 46,XX women, and 46,XY women with complete androgen insensitivity (CAIS).
• Men showed greater amygdala activation to sexual images than did typical women or women with completely androgen insensitivity.
• Typical women and women with CAIS were highly similar in their patterns of brain activation.
• Sex differences in brain activation to sexual images are not due to the presence of a Y chromosome.
• Aromatization of testosterone to estradiol does not appear to play a role in masculinization of responses to sexual stimuli

Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images. We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls.