Developmental basis of male nipple loss and retention in mammals

Most male mammals, including humans, have nipples, but a few male species, including mice, do not. It is currently believed that testosterone produced by the fetal testes during sexual differentiation causes nipple atrophy in male mice. However, since all male mammals produce testosterone during sexual differentiation, how nipples are retained in most male mammals, including humans, remains unknown. This study compared mammary gland development and hormonal regulation between guinea pigs and mice and found that androgen receptor (AR) is exclusively present in the developing mammary glands of mice during sexual differentiation. In mice, testosterone binds to AR, activating androgen-responsive genes and inducing apoptosis and autophagy in epithelial cells of the nipple bud, leading to nipple atrophy. During guinea pig embryonic development, the absence of the AR inactivates AR pathway genes and activates Wnt pathway genes, promoting cell proliferation and inhibiting programmed cell death, thereby inducing nipple formation.