Gonadal dysgenesis If a single or combination of these genes are mutated or deleted, downstream signalling is disrupted, leading to malformation of male external genitalia. SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation. An absence in SRY causes SOX9 to not be expressed at the appropriate time or concentration, leading to a deficiency in testosterone and Anti-Müllerian hormone production. Inadequate levels of testosterone and Anti-Müllerian hormone disrupts the development of Wolffian ducts and internal genitalia that are key to male reproductive tract development. The lack of the male associated steroid hormones drives Müllerian duct development and perusal
Transgender hormone therapy (male-to-female) suggesting a protective role of the male sex-determination chromosome. On the other hand, men with Klinefelter's syndrome (two X chromosomes and one Y chromosome), which causes hypoandrogenism, hyperestrogenism, and a very high incidence of gynecomastia (80%), have a dramatically (20- to 58-fold) increased risk of breast cancer compared to men with one X chromosome, closer to the rate of homogametic females. The incidences of breast cancer in karyotypical men (46,XY karyotype), men with Klinefelter's syndrome (47,XXY karyotype), and karyotypical women (46,XX karyotype) are approximately 0.1%, 3%, and 12.5%, respectively. Individuals with the 46,XY karyotype affected by complete androgen insensitivity syndrome