Defeminization

Abstract: Two clearly opposing views exist on the function of alpha-fetoprotein (AFP), a fetal plasma protein that binds estrogens with high affinity, in the sexual differentiation of the rodent brain. AFP has been proposed to either prevent the entry of estrogens or to actively transport estrogens into the developing female brain. The availability of Afp mutant mice (Afp(-/-)) now finally allows us to resolve this longstanding controversy concerning the role of AFP in brain sexual differentiation, and thus to determine whether prenatal estrogens contribute to the development of the female brain. Here we show that the brain and behavior of female Afp(-/-) mice were masculinized and defeminized. However, when estrogen production was blocked by embryonic treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione, the feminine phenotype of these mice was rescued. These results clearly demonstrate that prenatal estrogens masculinize and defeminize the brain and that AFP protects the female brain from these effects of estrogens.

Abstract: Prenatal-onset classical congenital adrenal hyperplasia (CAH) in 46,XX individuals is associated with variable masculinization/defeminization of the genitalia and of behavior, presumably both due to excess prenatal androgen production. The purpose of the current study was threefold: (1) to extend the gender-behavioral investigation to the mildest subtype of 46,XX CAH, the non-classical (NC) variant, (2) to replicate previous findings on moderate and severe variants of 46,XX CAH using a battery of diversely constructed assessment instruments, and (3) to evaluate the utility of the chosen assessment instruments for this area of work. We studied 63 women with classical CAH (42 with the salt wasting [SW] and 21 with the simple virilizing [SV] variant), 82 women with the NC variant, and 24 related non-CAH sisters and female cousins as controls (COS). NC women showed a few signs of gender shifts in the expected direction, SV women were intermediate, and SW women most severely affected. In terms of gender identity, two SW women were gender-dysphoric, and a third had changed to male in adulthood. All others identified as women. We conclude that behavioral masculinization/defeminization is pronounced in SW-CAH women, slight but still clearly demonstrable in SV women, and probable, but still in need of replication in NC women. There continues a need for improved instruments for gender assessment.